Pyrrolopyrimidine compound or salt thereof and compositions containing the pyrrolopyrimidine compound or salt thereof

ABSTRACT

A pyrrolopyrimidine compound or a salt thereof and compositions, NAE inhibitors and anti-tumor agents containing the pyrrolopyrimidine compound or a salt thereof. The pyrrolopyrimidine compound or a salt thereof has an NAE inhibitory action and a cell growth inhibitory effect and is represented by Formula (A):

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 15/122,863, filed Aug.31, 2016, which is a 35 U.S.C. 371 National Phase Entry Application fromPCT/JP2015/068218, filed Jun. 24, 2015, which claims priority to thespecification of Japan Patent Application No. 2014-129740 filed on Jun.24, 2014, and the specification of Japan Patent Application No.2015-024785 filed on Feb. 10, 2015 the disclosures of which areincorporated herein in their entirety by reference. The presentinvention relates to a novel pyrrolopyrimidine compound or a saltthereof, and a pharmaceutical composition comprising thepyrrolopyrimidine compound, in particular, a prophylactic agent and/or atherapeutic agent for tumors etc. based on an NAE inhibitory action.

TECHNICAL FIELD Background Art

A protein group called ubiquitin-like protein (Ubl), typified byubiquitin, binds to corresponding activating enzyme E1 and transferaseE2 to be added to a target protein through a covalent bond, therebyexerting influences on various characteristics such as target enzymeactivity, stability, intracellular localization, and the like(Non-patent Document 1).

Nedd8, a kind of Ubl, is activated by APPBP1-UBA3 heterodimer, which isa Nedd8-activating enzyme (NAE), in an ATP-dependent manner. Theactivated Nedd8 is subsequently transferred to E2 (Ubc12), and is thenadded to a series of target proteins called cullin. It is calledneddylation that Nedd8 is conjugated to a target protein. Theneddylation with respect to cullin promotes the activity (ability to addubiquitin to a ligase substrate) of cullin-RING ligases (CRL), whichfunction by forming a complex with cullin family protein and adaptorprotein. The protein group ubiquitinated by CRL is degraded in theproteasome. Many proteins are known as CRL substrates that regulate cellcycles and conduct intracellular signal transduction, and that arereported to be decreased expression in tumors; examples of such proteinsinclude p27, p21, and phosphorylated Iκ-B (Non-patent Documents 2 and3). More specifically, NAE contributes to tumor cell growth and survivalby facilitating ubiquitination and degradation by proteasome of the CRLsubstrate protein group through Nedd8 activation.

Because of the physiological function of NAE, an NAE inhibitor has acharacteristic property of simultaneously affecting a plurality ofsignaling pathways involved in the survival and growth of tumors. Thus,NAE inhibitors are expected to serve as a therapeutic agent having broadand effective antitumor actions.N-[(1S)-1-indanyl]-7-[(1R)-3α-hydroxy-4α-(sulfamoyloxymethyl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(hereinafter referred to as “MLN4924”) and the like have been known as acompound that inhibits the Nedd8-activating function of NAE (PatentDocument 1). MLN4924 is a compound having a pyrrolopyrimidine skeleton,and is characterized by having a substituted amino group at 4-position.MLN4924 causes accumulation of the CRL substrate protein group throughneddylation inhibition, thereby inducing cell growth arrest andapoptosis (Non-patent Document 4). Currently, the development of MLN4924as an antitumor agent has been advanced (Patent Document 2); and, inaddition to the use of MLN4924 alone, tests using a combination ofMLN4924 and other various anticancer drugs have also been conducted(Non-patent Documents 5 and 6). However, a great deal of the MLN4924administered is transferred to red blood cells in the blood; thus, anissue of decrease in plasma concentration from the concentrationrequired for ensuring the original medicinal effects of MLN4924 has beenidentified (Non-patent Document 6). Further, since MLN4924 inhibitscarbonic anhydrase II, which is highly expressed even in normal organs,such as red blood cells, kidneys, brain, and eyes, there is a concernthat MLN4924 induces side effects, specifically, electrolyteabnormality, hypotonia bulbi, metabolic acidosis, polyuria, urinarycalculus, and dysesthesia (Non-patent Document 8). Under suchcircumstances, a new NAE inhibitor that ensures NAE inhibitory activity,but that has a smaller carbonic anhydrase II inhibitory effect, has beendesired.

CITATION LIST Patent Documents

-   Patent Document 1: International Publication No. WO2006084281-   Patent Document 2: International Publication No. WO2012061551

Non-Patent Documents

-   Non-patent Document 1: Nature Rev Mol Cell Biol, 2009, 10 (5):    319-31.-   Non-patent Document 2: Genes & Cancer, 20101; 1 (7): 690-699-   Non-patent Document 3: Journal of Cellular Physiology, 2000, 183,    10-17-   Non-patent Document 4: Nature, 2009, 9; 458 (7239): 732-6-   Non-patent Document 5: Mol Cancer Ther, 2014, 13 (6); 1623-1635-   Non-patent Document 6: Mol Cancer Ther, 2012, 11 (4): 942-951-   Non-patent Document 7: 9th International ISSX Meeting Abstract, p.    108-   Non-patent Document 8: Israel Medical Association Journal, 2003, 5,    April, 260-263

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novelpyrrolopyrimidine compound or a salt thereof having NAE inhibitoryaction, a cell growth inhibitory effect, and attenuated carbonicanhydrase II inhibitory activity. Another object of the presentinvention is to provide a pharmaceutical preparation useful forpreventing and/or treating NAE-related diseases, particularly tumors,based on its NAE inhibitory action.

Solution to Problem

The present inventors conducted extensive research on compounds havingan NAE inhibitory action, and found that a novel compound represented byFormula (A) below, which is characterized by comprising a vinylenegroup, an ethynylene group, an arylene group, or a heteroarylene groupat 5-position (R₃ in Formula (A)) of the pyrrolopyrimidine skeleton, ora salt thereof, has superior NAE inhibitory action as well as a superiorcell growth inhibitory effect against tumor cell lines. The inventorsfurther found that the compound or a salt thereof has attenuatedcarbonic anhydrase II inhibitory activity. With these findings, theinventors completed the present invention.

wherein:

is a single bond or a double bond;

X is —O—, —CH₂—, or —CH═;

Y is —NH— or —O—;

R₁ is hydrogen, fluorine, a hydroxy group, a cyano group, or an aminogroup;

R₂ is hydrogen, fluorine, a hydroxy group, a cyano group, or an aminogroup;

R₃ is a vinylene group, an ethynylene group, a C6-C14 arylene group, ora monocyclic or bicyclic heteroarylene group having at least oneheteroatom selected from the group consisting of N, S and O;

R₄ is a bond, a methylene group, or a C3-C7 cycloalkylidene group;

R₅ is a C3-C7 saturated cycloalkyl group that may have one or more R₆, aC6-C10 unsaturated cycloalkyl group that may have one or more R₆, or amonocyclic or bicyclic unsaturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have one or more R₆;

R₆ is

halogen,a hydroxy group,a cyano group,a C1-C6 alkyl group that may have one or more phenoxy group as asubstituent,a carbamoyl group,a C1-C6 alkoxycarbonyl group,a monocyclic or bicyclic unsaturated heterocycloalkyl group having atleast one heteroatom selected from the group consisting of N, S and O,a monocyclic or bicyclic saturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have, one or more of either halogen, hydroxy group,carboxyl group, or C1-C6 alkyl group, as a substituent,an amino group,a mono- or di-(C1-C4 alkyl) amino group that may have one or morehydroxy group or phenyl group as a substituent,a C1-C6 alkoxy group that may have one or more of either halogen,C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S and O as a substituent, a benzyloxy group thatmay have one or more carbamoyl group as a substituent,a C1-C6 alkylthio group,a C1-C6 alkylsulfonyl group, oran aminosulfonyl group,

when two or more R₆ are present, the plurality of R₆ may be the same ordifferent.

Advantageous Effects of Invention

The present invention provides a novel compound or a salt thereofrepresented by Formula (A) above. The novel compound is useful as an NAEinhibitor.

It was clarified that the compound of the present invention or a saltthereof has superior NAE inhibitory activity, and inhibits growth oftumor cells. Further, since the carbonic anhydrase II inhibitoryactivity of the compound of the present invention or a salt thereof isattenuated, the effect of the decrease in plasma concentration due tothe transfer to the red blood cells will not occur. Therefore, thecompound of the present invention or a salt thereof is significantlyuseful as an agent for preventing and/or treating Tumors.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the growth inhibitory effects of the compound obtained inExample 1 on HCT-116.

FIG. 2 shows the body weight change caused by the compound obtained inExample 1.

FIG. 3 shows the growth inhibitory effects of the compound obtained inExample 55 on HCT-116.

FIG. 4 shows the body weight change caused by the compound obtained inExample 55.

FIG. 5 shows the growth inhibitory effects of the compound obtained inExamples 122 and 64 on CCRF-CEM.

FIG. 6 shows the body weight change caused by the compound obtained inExamples 122 and 64.

DESCRIPTION OF EMBODIMENTS

The groups in the composition represented by Formula (A) are describedbelow.

In Formula (A), the “C6-C14 arylene group” represented by R₃ is amonocyclic or polycyclic bivalent aromatic hydrocarbon group having 6 to14 carbon atoms. More specifically, examples of C6-C14 arylene groupinclude phenylene group, naphthylene group, and tetrahydronaphthylenegroup. A phenylene group or naphthylene group is preferable.

In Formula (A), “a monocyclic or bicyclic heteroarylene group having atleast one heteroatom selected from the group consisting of N, S and O”represented by R₃ is a monocyclic or bicyclic heteroarylene group having1 to 3 of at least one kind of heteroatom selected from the groupconsisting of N, S and O. Examples include thiazolylene group,pyrazolylene group, imidazolylene group, thienylene group, furylenegroup, pyrrolylene group, oxazolylene group, isoxazolylene group,isothiazolylene group, thiadiazolylene group, triazolylene group,tetrazolylene group, pyridylene group, pyrazylene group, pyrimidinylenegroup, pyridazinylene group, indolylene group, isoindolylene group,indazolylene group, triazolopyridilene group, benzimidazolilene group,benzoxazolylene group, benzothiazolylene group, benzothienylene group,benzofuranylene group, purinylene group, quinolylene group,isoquinolylene group, quinazolinylene group, quinoxalylene group,methylenedioxy phenylene group, ethylenedioxy phenylene group, dihydrobenzofuranylene group, benzoxazinylene group, dihydrobenzoxazinylenegroup, chromanylene group, thiochromanylene group,1,1-dioxythiochromanylene group, dihydro benzothienylene group, and1,1-dioxydihydro benzothienylene group. Preferable examples include amonocyclic heteroarylene group having 1 to 3 of at least one kind ofheteroatom selected from the group consisting of N, S, and O. Morepreferable examples include a monocyclic 5-membered heteroarylene grouphaving 1 or 2 of at least one kind of heteroatom selected from the groupconsisting of N, S, and O. Particularly preferable examples includethiazolylene group, pyrazolylene group, imidazolylene group, thienylenegroup, and oxazolylene group.

In Formula (A), the “C3-C7 cycloalkylidene group” is a monocyclicsaturated alkylidene group having 3 to 7 carbon atoms. Examples includethe compounds below.

Cyclopropylidene group

Cyclobutylidene group

Cyclopentylidene group

Cyclohexylidene group

Cycloheptylidene group

Preferable examples include a cyclopropylidene group.

In the present specification, the “cycloalkyl group” refers to asaturated or unsaturated monovalent cyclic hydrocarbon group. Unlessotherwise specified, the term “cycloalkyl” encompasses a monocycliccycloalkyl, and a polycyclic cycloalkyl such as bicyclic or tricycliccycloalkyl.

In the present specification, the “heterocycloalkyl group” refers to asaturated or unsaturated monovalent heterocyclic group. Unless otherwisespecified, the term “heterocycloalkyl” encompasses a monocyclicheterocycloalkyl, and a polycyclic heterocycloalkyl such as bicyclic ortricyclic heterocycloalkyl.

In Formula (A), the C3-C7 saturated cycloalkyl group of the “C3-C7saturated cycloalkyl group that may have one or more R₆” represented byR₅ refers to a cyclic saturated hydrocarbon group having 3 to 7 carbonatoms. Examples include cyclopropyl group, cyclobutyl group, cyclopentylgroup, cyclohexyl group, and cycloheptyl group. Preferable examplesinclude cyclohexyl group.

In Formula (A), the C6-C10 unsaturated cycloalkyl group of the “C6-C10unsaturated cycloalkyl group that may have one or more R₆” representedby R₅ is a monocyclic or bicyclic unsaturated hydrocarbon group having 6to 10 carbon atoms. Examples include phenyl group, naphthyl group,tetrahydronaphthyl group, and 2,3-dihydroindenyl group. Preferableexamples include phenyl group, naphthyl group, and 2,3-dihydroindenylgroup.

In Formula (A), examples of the monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O of the “monocyclic or bicyclicunsaturated heterocycloalkyl group that has at least one heteroatomselected from the group consisting of N, S, and O, and that may have oneor more R₆” represented by R₅ include hexamethyleneimino group,imidazolyl group, thienyl group, furyl group, pyrrolyl group, oxazolylgroup, isooxazolyl group, thiazolyl group, isothiazolyl group, pyrazolylgroup, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group,pyrimidinyl group, pyridazinyl group, indolyl group, isoindolyl group,indazolyl group, methylenedioxy phenyl group, ethylene dioxyphenylgroup, benzofuranyl group, dihydro benzofuranyl group, benzimidazolylgroup, benzooxazolyl group, benzothiazolyl group, purinyl group,quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinylgroup, 1H-pyrazolo[4,3-b]pyridin-5-yl group, 2,3-dihydro-1,4-benzoxazinogroup, 1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, and 1,1-dioxo-2,3-dihydro benzothiophen-7-ylgroup. Preferable examples include a monocyclic or bicyclic 5 to10-membered unsaturated heterocycloalkyl group having 1 to 3 of at leastone kind of heteroatom selected from the group consisting of N, S, andO. More preferable examples include thienyl group, pyridyl group,pyrazyl group, quinolyl group, isoquinolyl group,1H-pyrazolo[4,3-b]pyridin-5-yl group, 2,3-dihydro-1,4-benzoxazino group,1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, and 1,1-dioxo-2,3-dihydro benzothiophen-7-ylgroup.

In Formula (A), examples of the “halogen” represented by R₆ includefluorine, chlorine, bromine, and iodine. Preferable examples includefluorine and chlorine.

In Formula (A), the C1-C6 alkyl group of the “C1-C6 alkyl group that mayhave one or more phenoxy group as a substituent” represented by R₆refers to a linear or branched alkyl group having 1 to 6 carbon atoms.Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, and hexyl. Methyl is preferable.

In Formula (A), the C1-C6 alkoxy group of the “C1-C6 alkoxy group thatmay have one or more of either halogen, C3-C7 saturated cycloalkylgroup, or monocyclic or bicyclic unsaturated heterocycloalkyl grouphaving at least one heteroatom selected from the group consisting of N,S, and O as a substituent” represented by R₆ refers to a linear orbranched alkoxy group having 1 to 6 carbon atoms. Examples includemethoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxygroup, isobutoxy group, and tert-butoxy group. Methoxy group, ethoxygroup, n-propoxy group, and isopropoxy group are preferable.

In Formula (A), the halogen of the “C1-C6 alkoxy group that may have oneor more of either halogen, C3-C7 saturated cycloalkyl group, ormonocyclic or bicyclic unsaturated heterocycloalkyl group having atleast one heteroatom selected from the group consisting of N, S, and Oas a substituent” represented by R₆ refers to the halogens listed above,and is preferably fluorine. The number of substituted halogens is 1 to3, preferably 2 or 3.

In Formula (A), the C3-C7 saturated cycloalkyl group of the “C1-C6alkoxy group that may have one or more of either halogen, C3-C7saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O, as a substituent” represented by R₆refers to a saturated cycloalkyl group having 3 to 7 carbon atoms.Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, and cycloheptyl group. Cyclopropyl group ispreferable. The number of substituted saturated cycloalkyl groups ispreferably 1.

In Formula (A), the monocyclic or bicyclic unsaturated heterocycloalkylgroup having at least one heteroatom selected from the group consistingof N, S, and O of the “C1-C6 alkoxy group that may have one or more ofeither halogen, C3-C7 saturated cycloalkyl group, or monocyclic orbicyclic unsaturated heterocycloalkyl group having at least oneheteroatom selected from the group consisting of N, S, and O, as asubstituent” represented by R₆ refers to the unsaturatedheterocycloalkyl group described above. Preferable examples include amonocyclic unsaturated heterocycloalkyl group having 1 to 3 of at leastone kind of heteroatom selected from the group consisting of N, S, andO. More preferable examples include a monocyclic 5 or 6-memberedunsaturated heterocycloalkyl group having 1 or 2 of at least one kind ofheteroatom selected from the group consisting of N, S, and O.Particularly preferable examples include pyrazolyl group, triazolylgroup, and pyridyl group. The number of substituted unsaturatedheterocycloalkyl groups is preferably 1.

In Formula (A), preferable examples of the “C1-C6 alkoxy group that mayhave one or more of either halogen, C3-C7 saturated cycloalkyl group, ormonocyclic or bicyclic unsaturated heterocycloalkyl group having atleast one heteroatom selected from the group consisting of N, S, and O,as a substituent” represented by R₆ include methoxy group, difluoromethoxy group, trifluoro methoxy group, cyclopropyl methoxy group,3-pyridyl methoxy group, pyrazol-1-ylmethoxy group, ethoxy group,2,2,2-trifluoro ethoxy group, n-propoxy group, and isopropoxy group.

In Formula (A), preferable examples of the “benzyloxy group that mayhave one or more carbamoyl groups as a substituent” represented by R₆include benzyloxy group, and 3-carbamoyl benzyloxy group.

In Formula (A), the mono- or di-(C1-C4 alkyl) amino group of the “mono-or di-(C1-C4 alkyl) amino group that may have one or more hydroxy groupor phenyl group as a substituent” represented by R₆ refers to, among theabove C1-C6 alkyl groups, an amino group monosubstituted ordisubstituted with a C1-C4 alkyl group. Examples include methylaminogroup, ethylamino group, diethylamino group, methylethylamino group,isopropylamino group, cyclobutylmethylamino group, and dimethylaminogroup. Preferably examples include methylamino group, ethylamino group,dimethylamino group, and isopropylamino group.

In Formula (A), the “mono- or di-(C1-C4 alkyl) amino group that may haveone or more hydroxy group or phenyl group as a substituent” representedby R₆ is preferably methylamino group, ethylamino group, isopropylaminogroup, hydroxyethylamino group, dimethylamino group, orphenylmethylamino group (benzylamino group).

In Formula (A), the “C1-C6 alkoxycarbonyl group” represented by R₆refers to a carbonyl group substituted with the above alkoxy group.Examples include methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, isopropoxycarbonyl group,1-methylpropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonylgroup, tert-butoxycarbonyl group, 2-methyl-butoxycarbonyl group,neopentyloxycarbonyl group, and pentan-2-yloxycarbonyl group.Methoxycarbonyl group is preferable.

In Formula (A), the “monocyclic or bicyclic unsaturated heterocycloalkylgroup having at least one heteroatom selected from the group consistingof N, S, and O” represented by R₆ refers to the unsaturatedheterocycloalkyl group described above, preferably a monocyclic 5 or6-membered unsaturated heterocycloalkyl group having 1 or 2 of at leastone kind of heteroatom selected from the group consisting of N, S and O,and more preferably pyridyl group.

In Formula (A), examples of the monocyclic or bicyclic saturatedheterocycloalkyl group that has at least one heteroatom selected fromthe group consisting of N, S, and O of the “monocyclic or bicyclicsaturated heterocycloalkyl group that has at least one heteroatomselected from the group consisting of N, S, and O, and that may have oneor more of either halogen, hydroxy group, carboxyl group or C1-C6 alkylgroup as a substituent” represented by R₆ include azetidinyl group,pyrrolidinyl group, piperidinyl group, 2-oxo-1-pyrrolidinyl group,4-oxo-1-piperidinyl group, piperazinyl group, hexamethyleneimino group,morpholino group, thiomorpholino group, 1,1-dioxo-thiomorpholino group,homopiperazinyl group, tetrahydrofuranyl group, tetrahydropyranyl group,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group, and3-oxa-8-azabicyclo[3.2.1]octan-8-yl group. Preferable examples include amonocyclic or bicyclic 5 to 10-membered saturated heterocycloalkyl grouphaving 1 to 4 of at least one kind of heteroatom selected from the groupconsisting of N, S, and O. More preferable examples include azetidinylgroup, pyrrolidinyl group, piperidinyl group, piperazinyl group,2-oxo-1-pyrrolidinyl group, 4-oxo-1-piperidinyl group, morpholino group,thiomorpholino group, 1,1-dioxo-thiomorpholino group,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group, and3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.

In Formula (A), the halogen of the “monocyclic or bicyclic saturatedheterocycloalkyl group that has at least one heteroatom selected fromthe group consisting of N, S, and O, and that may have one or more ofeither halogen, hydroxy group, carboxyl group or C1-C6 alkyl group as asubstituent” represented by R₆ refers to the halogen listed above,preferably fluorine, chlorine, etc., and more preferably fluorine.

In Formula (A), examples of the C1-C6 alkyl group of the “monocyclic orbicyclic saturated heterocycloalkyl group that has at least oneheteroatom selected from the group consisting of N, S, and O, and thatmay have one or more of either halogen, hydroxy group, carboxyl group orC1-C6 alkyl group as a substituent” represented by R₆ include, among theabove alkyl groups, an alkyl group having 1 to 6 carbon atoms,preferably a methyl group.

In Formula (A), preferable examples of the “monocyclic or bicyclicsaturated heterocycloalkyl group that has at least one heteroatomselected from the group consisting of N, S, and O, and that may have oneor more of either halogen, hydroxy group, carboxyl group or C1-C6 alkylgroup as a substituent” represented by R₆ include azetidinyl group,3-hydroxy azetidin-1-yl group, pyrrolidinyl group,3-fluoropyrrolidin-1-yl group, 3-hydroxy pyrrolidin-1-yl group,3-carboxy-1-pyrrolidin-1-yl group, piperidinyl group,4-oxo-1-piperidinyl group, 3-hydroxy-1-piperidinyl group, piperazinylgroup, 4-methyl piperazin-1-yl group, 4-oxo-1-piperidinyl group,morpholino group, thiomorpholino group, 1,1-dioxo-thiomorpholino group,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group, and3-oxa-8-azabicyclo[3.2.1]octan-8-yl group.

In Formula (A), the “C1-C6 alkylthio group” represented by R₆ refers toa thio group having the above C1-C6 alkyl group, preferably a C1-C4alkylthio group, more preferably a methylthio group or an ethylthiogroup.

In Formula (A), the “C1-C6 alkylsulfonyl group” represented by R₆ refersto a sulfonyl group having the above C1-C6 alkyl group, preferably aC1-C4 alkylsulfonyl group, more preferably a methyl sulfonyl group or anethyl sulfonyl group.

Y in Formula (A) is —NH— or —O—, preferably —NH—.

R₁ in Formula (A) is hydrogen, fluorine, a hydroxy group, a cyano groupor an amino group, preferably hydrogen, fluorine or a hydroxy group,further preferably a hydroxy group.

R₂ in Formula (A) is hydrogen, fluorine, a hydroxy group, a cyano groupor an amino group, preferably hydrogen, fluorine, or a hydroxy group,further preferably hydrogen or a hydroxy group, particularly preferablya hydroxy group.

R₃ in Formula (A) is preferably an ethynylene group, or a monocyclicheteroarylene group having 2 of at least one kind of heteroatom selectedfrom the group consisting of N, S, and O, more preferably an ethynylenegroup.

R₄ in Formula (A) is preferably a bond.

R₅ in Formula (A) is preferably a C3-C7 saturated cycloalkyl group thatmay have one or more R₆, a C6-C10 unsaturated cycloalkyl group that mayhave one or more R₆, or a monocyclic or bicyclic unsaturatedheterocycloalkyl group that has at least one heteroatom selected fromthe group consisting of N, S, and O, and that may have one or more R₆.

More preferably, R₅ is a phenyl group or a naphthyl group that may besubstituted with one or more R₆, or a monocyclic or bicyclic unsaturatedheterocycloalkyl group that has at least one heteroatom selected fromthe group consisting of N, S and O, and that may have one or more R₆.

Further preferably, R₅ is a unsaturated heterocycloalkyl group or aphenyl group that may be substituted with one or more R₆, particularlypreferably a phenyl group, thienyl group, pyridyl group, pyrazyl group,quinolyl group, isoquinolyl group, 1H-pyrazolo[4,3-b]pyridin-5-yl group,2,3-dihydro-1,4-benzoxazino group,1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl group, 2,3-dihydrobenzothiophen-7-yl group, or 1,1-dioxo-2,3-dihydro benzothiophen-7-ylgroup that may be substituted with one or more R₆.

When R₅ is an unsaturated heterocycloalkyl group, R₅ is preferably a2,3-dihydro-1,4-benzoxazinyl group, a 3,4-dihydro-2H-thiochromen-8-ylgroup, a 2,3-dihydro benzothiophen-7-yl group or the like, morepreferably a 2,3-dihydro-1,4-benzoxazinyl group. The unsaturatedheterocycloalkyl groups listed above may be substituted with one or moreR₆.

When R₅ has R₆, the number of R₆ is, for example, 1 to 5, preferably 1to 3.

When R₅ has one or more R₆, R₆ is one of:

(i-1) halogen,(i-2) hydroxy group,(i-3) cyano group,(i-4) C1-C6 alkyl group that may have one or more phenoxy group as asubstituent,(i-5) carbamoyl group,(i-6) C1-C6 alkoxycarbonyl group,(i-7) monocyclic or bicyclic unsaturated heterocycloalkyl group havingat least one heteroatom selected from the group consisting of N, S, andO,(i-8) monocyclic or bicyclic saturated heterocycloalkyl group that hasat least one heteroatom selected from the group consisting of N, S, andO, and that may have one or more of either halogen, hydroxy group,carboxyl group, or C1-C6 alkyl group as a substituent,(i-9) amino group,(i-10) mono- or di-(C1-C4 alkyl) amino group that may have one or morehydroxy group or phenyl group as a substituent,(i-11) C1-6 alkoxy group that may have one or more of either halogen,C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O as a substituent,(i-12) benzyloxy group that may have one or more carbamoyl group as asubstituent,(i-13) C1-C6 alkylthio group,(i-14) C1-C6 alkylsulfonyl group,(i-15) aminosulfonyl group.

When R₅ has one or more R₆, R₆ in Formula (A) is more preferably one of:

(ii-1) halogen,(ii-2) hydroxy group,(ii-3) cyano group,(ii-4) C1-C6 alkyl group that may have one or more phenoxy group as asubstituent,(ii-5) carbamoyl group,(ii-6) C1-C6 alkoxycarbonyl group,(ii-7) monocyclic 5 or 6-membered unsaturated heterocycloalkyl grouphaving 1 or 2 of at least one kind of heteroatom selected from the groupconsisting of N, S, and O,(ii-8) monocyclic or bicyclic 5 to 10-membered saturatedheterocycloalkyl group that has 1 to 4 of at least one kind ofheteroatom selected from the group consisting of N, S, and O, and thatmay have one or more of either halogen, hydroxy group, carboxyl group,or C1-C6 alkyl group as a substituent,(ii-9) amino group,(ii-10) mono- or di-(C1-C4 alkyl) amino group that may have one or morehydroxy group or phenyl group, as a substituent,(ii-1) C1-6 alkoxy group that may have one or more of either halogen,C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O as a substituent,(ii-12) benzyloxy group that may have one or more carbamoyl group as asubstituent(ii-13) C1-C4 alkylthio group,(ii-14) C1-C4 alkylsulfonyl group, or(ii-15) aminosulfonyl group.

When R₅ has one or more R₆, R₆ in Formula (A) is more preferably one of:

(iii-1) fluorine, chlorine(iii-2) hydroxy group,(iii-3) cyano group,(iii-4) C1-C6 alkyl group that may have one or more phenoxy group as asubstituent,(iii-5) carbamoyl group,(iii-6) C1-C6 alkoxycarbonyl group,(iii-7) pyridinyl group,(iii-8) azetidinyl group, hydroxy azetidinyl group, thiomorpholinylgroup, dioxide thiomorpholinyl group, methyl piperazinyl group, hydroxypiperidinyl group, oxopiperidinyl group, piperidinyl group, hydroxypyrrolidinyl group, oxopyrrolidinyl group, pyrrolidinyl group, carboxylpyrrolidinyl group, fluoro pyrrolidinyl group, morpholinyl group,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group,3-oxa-8-azabicyclo[3.2.11]octan-8-yl group,(iii-9) amino group,(iii-10) methylamino group, ethylamino group, isopropylamino group,hydroxyethylamino group, dimethylamino group, phenyl methylamino group,(iii-11) C1-C6 alkoxy group that may have one or more of either halogen,C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O as a substituent,(iii-12) benzyloxy group that may have one or more carbamoyl group as asubstituent(iii-13) C1-C4 alkylthio group,(iii-14) C1-C4 alkylsulfonyl group, or(iii-15) aminosulfonyl group.

When R₅ has one or more R₆, R₆ in Formula (A) is more preferably one of:

(iv-1) fluorine, chlorine(iv-2) hydroxy group,(iv-3) cyano group,(iv-4) methyl group,(iv-7) 3-fluoro pyrrolidinyl group, morpholinyl group, thiomorpholinylgroup, 3-hydroxy azetidinyl group, azetidinyl group,(iv-9) amino group,(iv-10) methylamino group,(iv-11) C1-C6 alkoxy group that may have one or more of either halogenor C3-C7 saturated cycloalkyl group as a substituent, or(iv-13) C1-C4 alkylthio group.

When R₅ has one or more R₆, R₆ in Formula (A) is more preferably one of:

(v-1) fluorine,(v-4) methyl group,(v-7) saturated heterocycloalkyl group selected from the groupconsisting of 3-fluoro pyrrolidinyl, 3-hydroxy azetidinyl, andazetidinyl,(v-9) amino group,(v-10) methylamino group,(v-11) C1-C6 alkoxy group that may have one or more cyclopropyl group,or(v-13) C1-C4 alkylthio group.

When two or more R₆ are present, the plurality of R₆ may be the same ordifferent.

The compound represented by Formula (A) is preferably a compound havinghigh enzyme inhibitory activity against NAE that can generally be testedby a known method, more preferably, a compound such that theconcentration (IC₅₀) of the compound by which 50% of the enzyme can beinhibited is 0.03 μM or less, further preferably a compound having anIC₅₀ of 0.01 μM or less, particularly preferably a compound having anIC₅₀ of 0.003 μM or less.

The compound represented by Formula (A) is preferably a compound havinghigh tumor growth inhibitory activity that can generally be tested by aknown method, more preferably, a compound such that the concentration(IC₅₀) of the compound by which 50% of tumor growth can be inhibited is0.01 μM or less, particularly preferably a compound having an IC₅₀ of0.003 μM or less.

The compound represented by Formula (A) is preferably a compound havinga weak enzyme inhibitory activity against carbonic anhydrase II, andsaid activity can generally be tested by a known method. Morepreferably, the compound represented by Formula (A) is such that theconcentration (IC₅₀) of the compound by which 50% of the enzyme isinhibited is 0.03 μM or more, further preferably a compound having anIC₅₀ of 0.1 μM or more, further more preferably a compound having anIC₅₀ of 0.3 μM or more, and particular preferably a compound having IC₅₀of 1.0 μM or more.

Further preferable examples of the compound of the present inventioninclude a compound wherein in Formula (A), R₁ is hydrogen, fluorine, ora hydroxy group; R₂ is hydrogen, fluorine, or a hydroxy group; and R₃ isan ethynylene group, or a monocyclic or bicyclic heteroarylene grouphaving 1 to 4 of at least one kind of heteroatom selected from the groupconsisting of N, S, and O, or a salt thereof.

Further preferable examples of the compound of the present inventioninclude a compound wherein in Formula (A),

R₁ is a hydroxy group;R₂ is hydrogen or a hydroxy group;R₃ is an ethynylene group, or a monocyclic heteroarylene group having 2of at least one kind of heteroatom selected from the group consisting ofN, S and O;R₅ is a C3-C7 saturated cycloalkyl group that may have one or moreR₆; a C6-C10 unsaturated cycloalkyl group that may have one or more R₆;or a monocyclic or bicyclic unsaturated heterocycloalkyl group that hasat least one heteroatom selected from the group consisting of N, S andO, and that may be substituted with one or more R₆;

R₆ is

halogen,a hydroxy group,a cyano group,a C1-C6 alkyl group that may have one or more phenoxy group as asubstituent,a carbamoyl group,a C1-C6 alkoxycarbonyl group,a monocyclic or bicyclic unsaturated heterocycloalkyl group having atleast one heteroatom selected from the group consisting of N, S and O,a monocyclic or bicyclic saturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have one or more of either halogen, hydroxy group, carboxylgroup, or C1-C6 alkyl group as a substituent,an amino group,a mono- or di-(C1-C4 alkyl) amino group that may have one or morehydroxy group or phenyl group,a C1-6 alkoxy group that may have, as a substituent, one or more ofeither halogen, C3-C7 saturated cycloalkyl group, or monocyclic orbicyclic unsaturated heterocycloalkyl group having at least oneheteroatom selected from the group consisting of N, S, and O as asubstituent,a benzyloxy group that may have one or more carbamoyl group as asubstituent,a C1-C4 alkylthio group,a C1-C4 alkylsulfonyl group, oran aminosulfonyl group,(when two or more R₆ are present, the plurality of R₆ may be the same ordifferent), or a salt thereof.

Further preferable examples of the compound of the present inventioninclude a compound wherein, in Formula (A), R₁ is a hydroxy group;

R₂ is hydrogen or a hydroxy group;R₃ is an ethynylene group, or a monocyclic heteroarylene group having 2of at least one kind of heteroatom selected from the group consisting ofN, S, and O;R₅ is a C3-C7 saturated cycloalkyl group that may have one or more R₆; aC6-C10 unsaturated cycloalkyl group that may have one or more R₆; or amonocyclic or bicyclic unsaturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have one or more R₆;R₆ is fluorine, chlorine, a hydroxy group, a cyano group, a C1-C6 alkylgroup that may have one or more phenoxy group as a substituent,a carbamoyl group, a C1-C6 alkoxycarbonyl group,a pyridinyl group that may have at least one substituent selected fromthe group consisting of halogen, hydroxy group, and C1-C4 alkyl group,a saturated heterocycloalkyl group selected from the group consisting ofazetidinyl group, hydroxy azetidinyl group, thiomorpholinyl group,dioxide thiomorpholinyl group, methyl piperazinyl group, hydroxypiperidinyl group, oxopiperidinyl group, piperidinyl group, hydroxypyrrolidinyl group, oxopyrrolidinyl group, pyrrolidinyl group, carboxylpyrrolidinyl group, fluoro pyrrolidinyl group and morpholinyl group,amino group, methylamino group, ethylamino group, isopropylamino group,hydroxyethylamino group, dimethylamino group, phenyl methylamino group,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group,3-oxa-8-azabicyclo[3.2.1]octan-8-yl group,a C1-C6 alkoxy group that may have one or more of either halogen, C3-C7saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O, as a substituent,a benzyloxy group that may have one or more carbamoyl group as asubstituent,a C1-C4 alkylthio group,a C1-C4 alkylsulfonyl group, oran aminosulfonyl group(when two or more R₆ are present, the plurality of R₆ may be the same ordifferent), or a salt thereof.

Further preferable examples of the compound of the present inventioninclude a compound wherein in Formula (A),

R₁ is a hydroxy group;R₂ is a hydroxy group;R₃ is an ethynylene group;R₄ is a bond;R₅ is a C6-C10 unsaturated cycloalkyl group that may have one or moreR₆, ora monocyclic or bicyclic unsaturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S and O,and that may have one or more R₆; and

R₆ is

fluorine,chlorine,a hydroxy group,a cyano group,a methyl group,a 3-fluoro pyrrolidinyl group,a morpholinyl group,a thiomorpholinyl group,a 3-hydroxy azetidinyl group,an azetidinyl group,an amino group,a methylamino group,a C1-C6 alkoxy group that may have one or more of either halogen, C3-C7saturated cycloalkyl group, ora C1-C4 alkylthio group as a substituent(when two or more R₆ are present, the plurality of R₆ may be the same ordifferent), or a salt thereof.

Further preferable examples of the compound of the present inventioninclude a compound wherein, in Formula (A), Y is —NH—;

R₁ is a hydroxy group;R₂ is a hydroxy group;R₃ is an ethynylene group;R₄ is a bond;R₅ is a phenyl group or a naphthyl group having one or more R₆, ora monocyclic or bicyclic unsaturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have one or more R₆; and R₆ is fluorine,a methyl group,3-fluoro pyrrolidinyl,3-hydroxy azetidinyl,azetidinyl,an amino group,a methylamino group,a C1-C6 alkoxy group that may have a cyclopropyl group, ora C1-C4 alkylthio group(when two or more R₆ are present, the plurality of R₆ may be the same ordifferent), or a salt thereof.

Specifically, preferable examples of the compound of the presentinvention include:

-   4-amino-5-[2-(2,6-difluoro    phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-(4-amino-2,6-difluoro-phenyl)    ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoro    pyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]thio    morpholine;-   4-amino-5-[2-[2,6-difluoro-4-(3-hydroxy    azetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-fluoro-6-(2,2,2-trifluoro    ethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine;-   8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2-(cyclopropyl    methoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-fluoro-phenyl)    ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;-   4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   [(2R,3S,4R,5R)-5-[4-amino-5-[2-(2,6-difluoro    phenyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl    sulfamate; and salts of these compounds,-   further preferably,-   4-amino-5-[2-(2,6-difluoro    phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-(4-amino-2,6-difluoro-phenyl)    ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoro    pyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2,6-difluoro-4-(3-hydroxy    azetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;-   4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-5-[2-[2-(cyclopropyl    methoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine;-   4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;-   4-amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine;    and salts of these compounds.

The method for producing the compound of the present invention isdescribed below.

The compounds of the present invention may be produced, for example,through the production methods below or the methods described in theExamples. However, the method for producing the compounds of the presentinvention is not limited to these reaction examples.

Production Method A

In the formula, Z¹ and Z² are the same or different, and each representshydrogen, fluorine, a hydroxy group, an amino group, a cyano group or aprotector thereof.

P₁ is a protecting group of an amino group.R₃ represents a vinylene group, an ethynylene group, a C6-C14 arylenegroup, or a monocyclic or bicyclic heteroarylene group having at leastone heteroatom selected from the group consisting of N, S, and O.R₄ represents a single bond, a methylene group, or a C3-C7cycloalkylidene.R₅ is a C3-C7 saturated cycloalkyl group that may be substituted withone or more R₆;a C6-C10 unsaturated cycloalkyl group that may be substituted with oneor more R₆; ora monocyclic or bicyclic unsaturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, O, andthat may be substituted with one or more R₆.

R₆ is

halogen;a hydroxy group;a cyano group;a C1-C6 alkyl group that may have one or more phenoxy group as asubstituent;a carbamoyl group, a C1-C6 alkoxycarbonyl group;a C4-C7 unsaturated cycloalkyl group that may have one or more of eitherhalogen, hydroxy group, C1-C4 alkyl group, or carbamoyl group as asubstituent;a monocyclic or bicyclic unsaturated heterocycloalkyl group having atleast one heteroatom selected from the group consisting of N, S, and O;a monocyclic or bicyclic saturated heterocycloalkyl group that has atleast one heteroatom selected from the group consisting of N, S, and O,and that may have one or more of either halogen, hydroxy group, oxogroup, carboxyl group, dioxide group, or C1-C6 alkyl group as asubstituent;an amino group;a mono- or di-(C1-C4 alkyl) amino group that may have one or morehydroxy group or phenyl group as a substituent;a C1-C6 alkoxy group having one or more of either halogen, C3-C7saturated cycloalkyl group, or monocyclic or bicyclic unsaturatedheterocycloalkyl group having at least one heteroatom selected from thegroup consisting of N, S, and O as a substituent; a benzyloxy group thatmay have one or more carbamoyl group as a substituent;a C1-C4 alkylthio group;a C1-C4 alkylsulfonyl group; or an aminosulfonyl group.

when two or more R₆ are present, the plurality of R₆ may be the same ordifferent.

represents —O—, —CH₂— or ═CH.

Step 1

This step produces Compound (2) using a compound represented by Formula(1) (in this specification, the compound represented by Formula (1) maybe simply referred to as Compound (1); similarly, compounds representedby Formulas 2 to 30 may be simply referred to as Compounds (2) to (30))as a raw material, through a Mitsunobu reaction using a nitrogennucleophile, and a subsequent deprotection reaction.

In Compound (1), when Z¹ and/or Z² represents a protector of a hydroxygroup, examples of the protector include dimethyl acetal group,benzylidene acetal group, benzoyl group, and tert-butyl dimethylsilyloxy group. Z¹ and Z² may form the structure below, or the like,

(wherein Ra are the same or different, and each represents hydrogen,methyl, ethyl, phenyl, cyclohexyl or cyclopentyl)

together with the carbon atoms bound thereto. Examples of nitrogennucleophile include phthalimide. When phthalimide is used as a nitrogennucleophile, the amount of phthalimide used is 1 to 10 moles, preferably1 to 5 moles, per mole of Compound (1).

The Mitsunobu reaction can generally be performed by a known method,such as, for example, the method described in Synthesis, p. 1 (1981); ora similar method.

Examples of azodicarboxylic acid esters used for the Mitsunobu reactioninclude diethyl azodicarboxylate and diisopropyl azodicarboxylate. Suchan azodicarboxylic acid ester can be used in an amount of 1 to 10 moles,and preferably 1 to 5 moles, per mole of Compound (1).

Examples of phosphine compounds used in the Mitsunobu reaction includetriphenylphosphine and tributylphosphine, and the amount of phosphinecompound used is 1 to 10 moles, preferably 1 to 5 moles, per mole ofCompound (1).

Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, toluene, N,N-dimethyl formamide, N,N-dimethylacetamide,dimethyl sulfoxide, and N-methylpyrrolidin-2-one. These solvents may beused alone, or in a mixture. The reaction time ranges from 0.1 to 100hours, preferably 0.1 to 24 hours. The reaction temperature ranges from0° C. to the boiling temperature of the solvent, preferably 0° C. to100° C. The removal of the protecting group of a nitrogen nucleophilecan generally be performed by a known method, such as the methoddescribed in Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons (1981); or a similar method.

The removal of the phthalimide group can be performed by using anisolated phthalimide intermediate or by directly using the Mitsunobureaction solution, with hydrazine, hydroxylamine, methylamine,ethylamine, n-butylamine, etc., as a deprotection reagent. The amount ofthe deprotection reagent is typically an equimolar to excessive molaramount per mole of Compound (1).

Examples of the solvent include alcohol solvents (ethanol, methanol,etc.), acetonitrile, dichloromethane, chloroform, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide,N,N-dimethylacetamide, and N-methylpyrrolidin-2-one. These solvents maybe used alone, or in a mixture. The reaction time ranges from 0.1 to 100hours, preferably 0.1 to 24 hours. The reaction temperature ranges from0° C. to the boiling temperature of the solvent, preferably 0° C. to100° C.

Step 2

This step produces Compound (3) by reacting a sulfamoyl-introducingreagent with Compound (2).

The sulfamoyl-introducing reagent can be obtained from commercialsuppliers, or can be produced through a known method using, for example,sulfamoyl chloride, 1-aza-4-azoniabicyclo[2.2.2]octane-4-ylsulphonyl(tert-butoxycarbonyl)azanide or the like. Theamount of the sulfamoyl-introducing reagent used is 1 to 10 moles,preferably 1 to 5 moles, per mole of Compound (2).

Examples of the protecting group of an amino group include C1-C6 alkylgroup, tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group,and propionyl group.

Examples of bases include triethylamine, diisopropylethylamine,pyridine, imidazole, and DBU. When a base is used, the amount of thebase is generally 1 to 30 moles, preferably 1 to 10 moles, per mole ofCompound (2).

Examples of the solvent include acetonitrile, dichloromethane,chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene,N,N-dimethyl formamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, and preferably from 0° C. to 100° C.

Step 3

Using Compound (3) as a raw material, this step produces Compound (4)through a coupling reaction (Sonogashira coupling, Suzuki-Miyauracoupling, etc.). This step may be performed through multiple steps asnecessary, and may suitably be combined with a protection reaction, adeprotection reaction.

For example, among various Compounds (4), a compound in which R₃ has analkynylene group may be obtained through a coupling (Sonogashira)reaction, using Compound (3) and a compound: H—C≡C—R₄-R₅ (wherein R₄ andR₅ are as defined above)

In this case, the compound: H—C≡C—R₄-R₅ (wherein R₄ and R₅ are asdefined above) can be obtained from commercial suppliers, or can beproduced through a known method. The amount of this compound is 1 to 10mole, preferably 1 to 3 mole, per mole of Compound (3).

This step can generally be performed by a known method, for example, themethod disclosed in Chemical Reviews, Vol. 107, p. 874 (2007). Forexample, this step can be performed in the presence of a transitionmetal catalyst and a base in a solvent that does not adversely affectthe reaction.

Examples of transition metal catalyst usable in this step includepalladium catalysts (e.g., palladium acetate,tris(dibenzylideneacetone)dipalladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, etc.). Asnecessary, a ligand (e.g., triphenylphosphine, tri-tert-butylphosphine,etc.) is added, and a copper reagent (e.g., copper iodide, copperacetate, etc.) is used as a cocatalyst. The amount of the transitionmetal catalyst varies depending on the type of catalyst. For example,the amount of the transition metal catalyst used is generally 0.0001 to1 mole, preferably 0.01 to 0.5 moles, per mole of Compound (4). Theamount of the ligand used is generally 0.0001 to 4 moles, preferably0.01 to 2 moles, per mole of Compound (4). The amount of the cocatalystused is generally 0.0001 to 4 moles, preferably 0.001 to 2 moles, permole of Compound (4).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate,sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide, or butyl lithium;and inorganic bases such as sodium hydrogen carbonate, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydroxide, and sodiumhydride. Among these, organic bases such as triethylamine anddiisopropylethylamine are preferable. The amount of the base used isgenerally 0.1 to 50 moles, and preferably 1 to 20 moles, per mole ofCompound (4).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, 1,4-dioxane, etc.), alcohols (e.g., methanol, ethanol,etc.), aprotic polar solvents (e.g., dimethylformamide,dimethylsulfoxide, hexamethyl phosphoramide, etc.), water, and mixturesthereof. The reaction time ranges from 0.1 to 100 hours, preferably 0.5to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 150° C.

Further, this step may also be performed through Suzuki-Miyaura couplingusing Compound (3) and an organic boron compound (boric-acid compound,boric-acid ester, etc.) having a substituent —R₃—R₄-R₅ (wherein R₃, R₄,and R₅ are as defined above)

In this method, the organic boron compound can be obtained fromcommercial suppliers, or can be produced through a known method. Theamount of the organic boron compound used is 1 to 10 moles, preferably 1to 3 moles, per mole of Compound (3).

In this method, the Suzuki-Miyaura coupling can generally be performedby a known method, such as the method described in Chemical Reviews,Vol. 95, p. 2457 (1995); or a similar method.

Examples of reaction catalyst used for the Suzuki-Miyaura couplinginclude tetrakis triphenylphosphine palladium (0), bis(triphenylphosphine)palladium(II) dichloride, and 1,1′-bis (diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex.The amount of the reaction catalyst used depends on the type of thecatalyst. The amount of the catalyst used is generally 0.0001 to 1 mole,preferably 0.01 to 0.5 moles, per mole of Compound (3).

Examples of the solvent include hydrocarbons (e.g., benzene, toluene,and xylene), nitriles (e.g., acetonitrile), ethers (e.g.,dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohols (e.g.,methanol, ethanol, etc.), aprotic polar solvents (e.g.,dimethylformamide, dimethylsulfoxide, etc.), and water. These solventsmay be used alone, or in a mixture. The reaction time ranges from 0.1 to100 hours, preferably 0.1 to 24 hours. The reaction temperature rangesfrom 0° C. to the boiling temperature of the solvent, preferably 0° C.to 100° C.

Step 4

This step produces Compound (5) by deprotecting the protected aminogroup of Compound (4). The deprotection can generally be performed by aknown method, such as the method described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons (1981); or a similarmethod. An example of the protecting group is tert-butyloxycarbonyl.When a tert-butyl oxycarbonyl group is used as a protecting group, thedeprotection is preferably performed under acidic conditions. Examplesof acids that can be used include hydrochloric acid, acetic acid,trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosic acid,and the like. The amount of the acid used is preferably 1 to 100 molesper mole of Compound (4).

Any solvent that does not adversely affect the reaction may be used forthe reaction. Examples of the solvent include alcohols (e.g., methanol),hydrocarbons (e.g., benzene, toluene, and xylene), halogenatedhydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane,etc.), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, etc.), aprotic polar solvents (e.g.,N,N-dimethylformamide, dimethylsulfoxide, hexamethyl phosphoramide,etc.), and mixtures thereof. The reaction time ranges 0.1 to 100 hours,preferably 0.5 to 24 hours. The reaction temperature ranges from 0 to120° C., preferably 0 to 90° C.

Compound (1) used as a raw material in Production Method A can beobtained from commercial suppliers, or can be produced through a knownmethod. For example, Compound (7) in which Z¹ and Z² in Formula 1represent a specific protector of a hydroxy group may be producedthrough Production Method B below.

Production Method B

wherein Ra are the same or different, and each represents hydrogen,methyl, ethyl, phenyl, cyclohexyl, or cyclopentyl.

Step 5

This step produces Compound (7) by protecting two hydroxy groups amongthe hydroxy groups of Compound (6). Examples of the protection reagentinclude dialkoxy alkane and the like. The amount of the protectionreagent used is 1 to 100 moles, preferably 1 to 10 moles, per mole ofCompound (6).

The protection can generally be performed by a known method, such as themethod described in Protective Groups in Organic Synthesis, T. W.Greene, John Wiley & Sons (1981); or a similar method.

Examples of the reaction catalyst include p-toluenesulfonic acid,methanesulfonic acid, pyridinium p-toluenesulfonates, perchloric acid,and sulfuric acid. When a reaction catalyst is used, the amount of thereaction catalyst depends on the type of the catalyst. For example, theamount of the reaction catalyst is generally 0.0001 to 1 mole,preferably 0.01 to 0.5 moles, per mole of Compound (6).

Examples of the solvent include acetonitrile, dichloromethane,chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Further, Compound (15) in which Z¹ and Z² in Formula 1 represent aspecific protector of a hydroxy group may be produced through ProductionMethod C below.

Production Method C

wherein P₂ is a protecting group of a hydroxy group. Ra is as definedabove.

Step 6

This step produces Compound (9) by protecting two hydroxy groups amongthe hydroxy groups of Compound (8). The protection reaction may beperformed in the same manner as in Step 5.

Step 7

This step produces an isomer mixture of Compound (10), which is apyrrolopyrimidine compound, by reacting an isomer mixture of Compound(9) and 2-(4,6-dichloro pyrimidin-5-yl)acetaldehyde in the presence of abase.

The amount of the 2-(4,6-dichloro pyrimidin-5-yl)acetaldehyde is 1 to 10moles, preferably 1 to 3 moles, per mole of Compound (9).

The reaction can generally be performed by a known method, for example,the method disclosed in Tetrahedron Letters, 26 (16), 2001-2 (1985).

Examples of bases include triethylamine, diisopropylethylamine,pyridine, lutidine, collidine, and DBU. When a base is used, the amountof the base is generally 1 to 100 moles, preferably 1 to 20 moles, permole of Compound (9).

Examples of the solvent include ethanol, 2-propanol, 2-butanol,acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Step 8

This step converts the isomer mixture of Compound (10) into Compound(11) consisting of only one of the isomers, in the presence of an acidcatalyst.

Examples of acids include p-toluenesulfonic acid, methanesulfonic acid,pyridinium p-toluene sulfonate, perchloric acid, and sulfuric acid. Theamount of the acid is generally 0.001 to 10 moles, preferably 0.01 to 2moles, per mole of Compound (10)

Examples of the solvent include acetone, 2-butanone, acetonitrile,dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 1 to48 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Step 9

This step protects the hydroxy group of Compound (11) using CompoundP₂—Cl (wherein P₂ is a protecting group of a hydroxy group).

The reaction can generally be performed by a known method, such as themethod described in Protective Groups in Organic Synthesis, T. W.Greene, John Wiley & Sons (1981); or a similar method.

The protecting group of a hydroxy group represented by P₂ in CompoundP₂—Cl is not particularly limited insofar as it has a protectingfunction. Examples include lower alkyl groups such as methyl, ethyl,propyl, isopropyl, and tert-butyl; lower alkylsilyl groups such astrimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groupssuch as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl;trimethylsilylethoxymethyl; aralkyl groups such as benzyl,p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, andtrityl; and acyl groups such as formyl, acetyl, and trifluoroacetyl. Inparticular, methyl, methoxymethyl, tetrahydropyranyl,trimethylsilylethoxymethyl, tert-butyldimethylsilyl, and acetyl arepreferable.

The compound can be obtained from commercial suppliers, or can beproduced through a known method. The amount of the compound is 1 to 20moles, preferably 1 to 5 moles, per mole of Compound (11)

Examples of the base include triethylamine, diisopropylethylamine,pyridine, lutidine, collidine, and DBU. The amount of the base isgenerally 1 to 20 moles, preferably 1 to 5 moles, per mole of Compound(11).

Examples of the solvent include acetonitrile, dichloromethane,chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Step 10

This step produces Compound (13) by reacting Compound (12) withiodosuccinimide, thereby introducing an iodine atom.

The iodination may be performed according to the method disclosed inInternational Publication WO2006/102079, or a similar method. The amountof the iodosuccinimide is 1 to 20 moles, preferably 1 to 5 moles, permole of Compound (12).

Examples of the solvent include acetone, acetonitrile, ethyl acetate,dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Step 11

This step produces Compound (14) by deprotecting the protected hydroxygroup of Compound (13).

The deprotection can generally be performed by a known method, such asthe method described in Protective Groups in Organic Synthesis, T. W.Greene, John Wiley & Sons (1981); or a similar method.

When a tert-butyl dimethylsilyl group is used as a protecting group,tetrabutylammonium fluoride, for example, is used as a deprotectionreagent. The amount of the reagent is preferably 1 to 10 moles, per moleof Compound (13).

Any solvent that does not adversely affect the reaction may be used forthe reaction. Examples of the solvent include ethers (e.g.,1,2-dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents(e.g., N,N-dimethylformamide, dimethylsulfoxide, hexamethyl phosphorylamide), etc.), and mixtures thereof. The reaction time ranges from 0.1to 100 hours, preferably 0.5 to 24 hours. The reaction temperatureranges from 0 to 80° C., preferably 0 to 50° C.

Step 12

This step produces Compound (15) by reacting Compound (14) with ammoniaor a salt thereof.

The amount of the ammonia or a salt thereof used in this step istypically an equimolar to excessive molar amount per mole of Compound(14).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include water, methanol, ethanol, isopropanol, tert-butylalcohol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylformamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, andmixtures thereof.

The reaction temperature is generally 0° C. to 200° C., preferably fromroom temperature to 150° C. The reaction time is generally 5 minutes to7 days, preferably 30 minutes to 72 hours.

Production Method D

Further, Compound (19), which is a compound in which Z¹ in Formula 1 isa hydroxy group, Z² is hydrogen, and X is CH₂, may be produced throughProduction Method D below.

Step 13

This step reacts Compound (16) with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde. This reaction may be performed in the samemanner as in Step 7.

Step 14

This step reacts the reaction product obtained in Step 13 withiodosuccinimide, thereby introducing an iodine atom. This reaction maybe performed in the same manner as in Step 10.

Step 15

This step produces Compound (19) by reacting the reaction productobtained in Step 14 with ammonia or a salt thereof. This reaction may beperformed in the same manner as in Step 12.

Compound (20)

Further, Compound (20), which is a compound in which Z¹ in Formula 1 isa hydroxy group, Z² is hydrogen, and X is O, is a publicly knowncompound.

Production Method E Further, among the compounds of the presentinvention, Compound (27) in which R₁ and R₂ are hydroxy groups, and

is ═CH— may be produced through Production Method E below.

wherein R₃, R₄, and R₅ are as defined above.

Step 16

This step produces Compound (22) by reducing the carboxyl group ofCompound (21). This step is performed in the presence of a reducingagent. In this step, the amount of the reducing agent is 1 to 20 moles,preferably 1 to 5 moles, per mole of Compound (21). Examples of thereducing agent include sodium borohydride, lithium aluminum hydride,borane reagent (e.g., diborane), and diisobutylaluminum hydride.

Examples of the solvent include methanol, ethanol, diethylether,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and toluene. Thesesolvents may be used alone, or in a mixture. The reaction time rangesfrom 0.1 to 100 hours, preferably 0.1 to 24 hours. The reactiontemperature ranges from 0° C. to the boiling temperature of the solvent,preferably 0° C. to 100° C.

Step 17

This step produces Compound (23) through a Mitsunobu reaction usingCompound (22) as a raw material, and4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a nucleophilic agent.

This reaction may be performed in the same manner as in Step 1.

Step 18

This step produces Compound (24) by reacting Compound (23) with ammoniaor a salt thereof. This reaction may be performed in the same manner asin Step 12.

Step 19

This step produces Compound (25) by deprotecting the protected hydroxygroup of Compound (24). This reaction may be performed in the samemanner as in Step 11.

Step 20

This step produces Compound (26) through a Mitsunobu reaction usingCompound (25) as a raw material, and tert-butyl sulfamoyl carbamate as anucleophilic agent.

This reaction may be performed in the same manner as in Step 1.

Step 21

This step produces Compound (27) using Compound (26) as a raw material,by deprotecting the protected amino group after a coupling reaction(Sonogashira coupling, Suzuki-Miyaura coupling, etc.). This reaction maybe performed in the same manner as in Step 3 and Step 4.

Production Method F

Further, among the compounds of the present invention, Compound (29) inwhich R₁ and R₂ are the same or different, and each represent hydrogen,fluorine, a hydroxy group, an amino group, a cyano group, or a protectorthereof may be produced through Production Method F below.

wherein X, R₃, R₄, R₅, Z¹, and Z² are as defined above.

Step 22

This step produces Compound (28) through a coupling reaction(Sonogashira coupling, Suzuki-Miyaura coupling, etc.) using Compound (1)as a raw material. This reaction may be performed in the same manner asin Step 3.

Step 23

This step produces Compound (29) by reacting Compound (28) with asulfamoyl-introducing reagent.

This reaction may be performed in the same manner as in Step 2. Thisstep may be performed through multiple steps as necessary, and maysuitably be combined with a deprotection reaction.

Production Method G Further, among the compounds of the presentinvention, Compound (32) may be produced through Production Method Gbelow.

wherein P1, Z¹, and Z² are as defined above. Rb is the same as R₆ above.Rc represents a substituted or unsubstituted alkyl group.

Step 24

This step produces Compound (31) by oxidizing Compound (30). This stepis performed in the presence of an oxidant. The amount of the oxidantused in this step is 1 to 20 moles, preferably 1 to 5 moles, per mole ofCompound (30). Examples of the oxidant include oxone, m-chloroperbenzoicacid, hydrogen peroxide, and potassium permanganate.

Examples of the solvent include water, acetone, 2-butanone,acetonitrile, ethyl acetate, dichloromethane, chloroform,tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, andN-methylpyrrolidin-2-one. These solvents may be used alone, or in amixture. The reaction time ranges from 0.1 to 100 hours, preferably 0.1to 24 hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0° C. to 100° C.

Step 25

This step produces Compound (32) by deprotecting the protected aminogroup of Compound (31). This reaction may be performed in the samemanner as in Step 4.

The compounds thus-obtained through Production Methods A to G can besubjected to the subsequent step after or without isolation andpurification by known separation and purification means, such asconcentration, vacuum concentration, crystallization, solventextraction, reprecipitation, and chromatography.

When the compound of the present invention has isomers such as opticalisomers, stereoisomers, regioisomers, and rotational isomers, any of theisomers and mixtures thereof is included within the scope of thecompound of the present invention. For example, when the compound hasoptical isomers, the optical isomer separated from a racemic mixture isalso included within the scope of the compound of the present invention.Each of such isomers can be obtained as a single compound by knownsynthesis and separation means (e.g., concentration, solvent extraction,column chromatography, recrystallization, etc.).

The compound of the present invention can be isolated and purified byusual isolation and purification means. Examples of such means includesolvent extraction, recrystallization, preparative reversed-phasehigh-performance liquid chromatography, column chromatography,preparative thin-layer chromatography, and the like.

The compound or a salt thereof of the present invention may be in theform of crystals. Single crystals and polymorphic mixtures are includedwithin the scope of the compound or a salt thereof of the presentinvention. Such crystals can be produced by crystallization according toa crystallization method known per se in the art. The compound or a saltthereof of the present invention may be a solvate (e.g., a hydrate) or anon-solvate. Any of such forms are included within the scope of thecompound or a salt thereof of the present invention. Compounds labeledwith an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I) are also included within thescope of the compound or a salt thereof of the present invention.

A prodrug of the compound of the present invention or of a salt thereofrefers to a compound that can be converted to the compound or a saltthereof of the present invention through a reaction with an enzyme,gastric acid, or the like, under physiological conditions in vivo, i.e.,a compound that can be converted to the compound or a salt thereof ofthe present invention by enzymatic oxidation, reduction, hydrolysis, orthe like; or a compound that can be converted to the compound or a saltthereof of the present invention by hydrolysis with gastric acid or thelike. Further, the prodrug of the compound or a salt thereof of thepresent invention may be compounds that can be converted to the compoundor a salt thereof of the present invention under physiologicalconditions, such as those described in “Iyakuhin no Kaihatsu[Development of Pharmaceuticals],” Vol. 7, Molecular Design, publishedin 1990 by Hirokawa Shoten Co., pp. 163-198.

The salt of the compound of the present invention refers to a commonsalt used in the field of organic chemistry. Examples of such saltsinclude base addition salts to carboxyl group when the compound hascarboxyl group, and acid addition salts to an amino or basicheterocycloalkyl group when the compound has an amino or basicheterocycloalkyl group.

Examples of base addition salts include alkali metal salts such assodium salts and potassium salts; alkaline earth metal salts such ascalcium salts and magnesium salts; ammonium salts; and organic aminesalts such as trimethylamine salts, triethylamine salts,dicyclohexylamine salts, ethanolamine salts, diethanolamine salts,triethanolamine salts, procaine salts, and N,N′-dibenzylethylenediaminesalts.

Examples of acid addition salts include inorganic acid salts such ashydrochlorides, sulfates, nitrates, phosphates, and perchlorates;organic acid salts such as acetates, formates, maleates, fumarates,tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonatessuch as methanesulfonates, isethionates, benzenesulfonates, andp-toluenesulfonates. Hydrochlorides are preferable.

The compound or a salt thereof of the present invention has superior NAEinhibitory activity and is useful as an antitumor agent. The type ofmalignant tumor to be treated by the compound or a salt thereof of thepresent invention is not particularly limited. Examples of malignanttumors include epithelial cancers (e.g., respiratory system cancers,digestive system cancers, reproductive system cancers, secretion systemcancers, and the like), sarcomas, hematopoietic tumors, central nervoussystem tumors, and peripheral nerve tumors.

Preferable examples include epithelial cancers, sarcomas, andhematopoietic tumors. More preferable examples include digestive systemcancers, sarcomas, and hematopoietic tumors. Further, the organ fromwhich the tumor is developed is not particularly limited. Examplesinclude head and neck cancers, esophagus cancer, gastric cancer, coloncancer, rectum cancer, liver cancer, gallbladder cancer,cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lungcancer, breast cancer, ovarian cancer, cervical cancer, endometrialcancer, renal cancer, bladder cancer, prostate cancer, testicular tumor,osteosarcoma, soft-tissue sarcoma, multiple myeloma, skin cancer, braintumor, and mesothelioma. Preferably, the target cancer is colon cancer,rectum cancer, pancreatic cancer, lung cancer, prostate cancer, breastcancer, osteosarcoma, soft-tissue sarcoma, or skin cancer.

Further, examples of hematopoietic tumors include bone marrow tumors(e.g., lymphocytic leukemia, myelogenous leukemia, acute leukemia,chronic leukemia, and the like), and lymphoid tumors.

Examples of bone marrow tumors include myeloproliferative neoplasm(MPN), acute myelogenous leukemia (AML), related precursor neoplasm,acute lymphocytic leukemia, chronic myelogenous leukemia (CML), andmyelodysplastic syndrome (MDS). Preferable examples include acuteleukemia. Particularly preferable examples include acute myelogenousleukemia.

Examples of lymphoid tumors include precursor lymphoid tumor, matureB-cell tumor, mature T-cell tumor and NK-cell tumor, and Hodgkin'slymphoma. Preferable examples include precursor lymphoid tumors, matureB-cell tumor, mature T-cell tumor and NK-cell tumor. Lymphoid tumorsthat are not regarded as Hodgkin's lymphoma may be collectively referredto as non-Hodgkin's lymphoma.

Examples of precursor lymphoid tumors include B-lymphoblasticleukemia/lymphoma, T-lymphoblastic leukemia/lymphoma (ALL), blasticNK-cell lymphoma, and like blastic lymphoma. T-lymphoblasticleukemia/lymphoma is preferable.

Examples of mature B-cell tumor include chronic lymphocyticleukemia/small lymphocytic lymphoma (CLL/SLL), B-cell prolymphocyticleukemia (B-PLL), splenic marginal zone lymphoma (SMZL), hairy cellleukemia (HCL), Waldenstrom's macroglobulinemia (WM), plasma cell tumor,MALT lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), B-celllymphoma (diffuse large B-cell lymphoma (DLBCL), and Burkitt'slymphoma). Plasma cell tumor and B-cell lymphoma are preferable.

Preferable examples of plasma cell tumor include multiple myeloma.

Examples of mature T-cell tumor and NK-cell tumor include T-cellprolymphocytic leukemia (T-PLL), aggressive NK-cell leukemia/lymphoma,adult T-cell leukemia/lymphoma, and peripheral T-cell lymphoma nototherwise specified (PTCL-NOS).

Examples of Hodgkin's lymphoma include nodular lymphocyte-predominantHodgkin's lymphoma, classical Hodgkin's lymphoma, nodular sclerosisclassical Hodgkin's lymphoma, and mixed cellularity classical Hodgkin'slymphoma.

FAB classification has been hitherto known for use in the diagnosis andclassification of hematopoietic tumors. In recent years, WHOclassification has also been used. The compound of the present inventionor a salt thereof is useful for the various hematopoietic tumorsclassified by both FAB classification and WHO classification.

When the compound or a salt thereof of the present invention is used asa pharmaceutical preparation, a pharmaceutical carrier can be added, ifrequired, thereby forming a suitable dosage form according to preventionand treatment purposes. Examples of the dosage form include oralpreparations, injections, suppositories, ointments, patches, eye-drops,and the like. Of these, injections (intravenous injections etc.) arepreferable. Such dosage forms can be formed by methods conventionallyknown to persons skilled in the art.

As the pharmaceutical carrier, various conventional organic or inorganiccarrier materials used as preparation materials may be blended as anexcipient, binder, disintegrant, lubricant, or coating agent in solidpreparations; or as a solvent, solubilizing agent, suspending agent,isotonizing agent, pH adjuster/buffer, or soothing agent in liquidpreparations. Moreover, pharmaceutical preparation additives, such asantiseptics, antioxidants, colorants, sweeteners, and stabilizers, mayalso be used, if required.

When a liquid preparation for oral administration is prepared, ataste-masking agent, a buffer, a stabilizer, a flavoring agent, and thelike, may be added to the compound of the present invention; and theresulting mixture may be formulated into an oral liquid preparation,syrup, elixir, etc., according to an ordinary method.

When a suppository is prepared, pharmaceutically acceptable carriersknown in the art, such as polyethylene glycol, lanolin, cacao butter,and fatty acid triglyceride; and as necessary, surfactants such as Tween80®, may be added to the compound of the present invention, and theresulting mixture may be formulated into a suppository according to anordinary method.

When an ointment is prepared, a commonly used base, stabilizer, wettingagent, preservative, and the like, may be blended into the compound ofthe present invention, as necessary; and the obtained mixture may bemixed and formulated into an ointment according to an ordinary method.

Examples of the base include liquid paraffin, white petrolatum, whitebeeswax, octyl dodecyl alcohol, paraffin, and the like.

Examples of excipients include lactose, sucrose, D-mannitol, starch,crystalline cellulose, calcium silicate, and the like.

Examples of binders include hydroxypropyl cellulose, methyl cellulose,polyvinylpyrrolidone, candy powder, hypromellose, and the like.

Examples of disintegrators include sodium starch glycolate, carmellosecalcium, croscarmellose sodium, crospovidon, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and the like.

Examples of lubricants include talc, magnesium stearate, sucrose fattyacid ester, stearic acid, sodium stearyl fumarate, and the like.

Examples of coating agents include ethyl cellulose, aminoalkylmethacrylate copolymer RS, hypromellose, sucrose, and the like.

Examples of solvents include water, propylene glycol, physiologicalsaline, and the like.

Examples of solubilizing agents include polyethylene glycol, ethanol,α-cyclodextrin, macrogol 400, polysorbate 80, and the like.

Examples of suspending agents include carrageenan, crystallinecellulose/carmellose sodium, polyoxyethylene hydrogenated castor oil,and the like.

Examples of isotonizing agents include sodium chloride, glycerin,potassium chloride, and the like.

Examples of pH adjuster/buffer include sodium citrate, hydrochloricacid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, and thelike.

Examples of soothing agents include procaine hydrochloride, lidocaine,and the like.

Examples of antiseptics include ethyl parahydroxybenzoate, cresol,benzalkonium chloride, and the like.

Examples of antioxidants include sodium sulfite, ascorbic acid, naturalvitamin E, and the like.

Examples of coloring agents include titanium oxide, iron sesquioxide,Food Blue No. 1, copper chlorophyll, and the like.

Examples of sweeteners include aspartame, saccharins, sucralose,1-menthol, mint flavor, and the like.

Examples of stabilizers include sodium pyrosulfite, edetate sodium,erythorbic acid, magnesium oxide, dibutylhydroxytoluene, and the like.

Examples of preservatives include methyl parahydroxybenzoate, ethylparahydroxybenzoate, propyl parahydroxybenzoate, and the like.

When a patch is prepared, the above-described ointment, cream, gel,paste, or the like, may be applied to an ordinary substrate according toan ordinary method.

As the substrate, woven fabrics or non-woven fabrics comprising cotton,staple fibers, or chemical fibers; and films or foam sheets of softvinyl chloride, polyethylene, polyurethane, etc., are suitable.

The amount of the compound of the present invention to be incorporatedin each of such dosage unit forms depends on the condition of thepatient to whom the compound is administered, the dosage form, etc. Ingeneral, in the case of an oral agent, an injection, and a suppository,the amount of the compound of the present invention is preferably 10mg/m² to 1000 mg/m² per dosage unit form.

The daily dose of the medicine in such a dosage form depends on thecondition, body weight, age, gender, etc., of the patient, and cannot begeneralized. For example, the daily dose of the compound of the presentinvention for an adult (body weight: 50 kg) may be generally 13.9 to1500 mg, and preferably 50 to 1000 mg; and is preferably administered inone dose, or in two to three divided doses, per day.

EXAMPLES

The following describes the present invention in more detail withreference to Examples. However, the scope of the present invention isnot limited to these Examples.

Commercially available reagents were used in the Examples, unlessotherwise specified.

For silica gel column chromatography, Purif-Pack (registered trademark)SI produced by Moritex Corp., KP-Sil (registered trademark) Silicaprepacked column produced by Biotage, or HP-Sil (registered trademark)Silica prepacked column produced by Biotage was used.

For basic silica gel column chromatography, Purif-Pack (registeredtrademark) NH produced by Moritex Corp or KP-NH (registered trademark)prepacked column produced by Biotage was used.

For preparative thin-layer chromatography, Kieselgel™ 60F 254, Art. 5744produced by Merck or NH₂ Silica Gel 60F254 Plate produced by Wako wasused.

NMR spectra were measured by using AL400 (400 MHz; produced by JEOL),Mercury 400 (400 MHz; produced by Agilent Technologies, Inc.) modelspectrometer, or Inova 400 (400 MHz; produced by Agilent Technologies,Inc.) model spectrometer equipped with an OMNMR probe (produced byProtasis). The measurement was carried out using tetramethylsilane as aninternal standard when tetramethylsilane was contained in a deuteratedsolvent; otherwise, an NMR solvent was used as an internal standard. Allthe δ values are shown by ppm.

The microwave reaction was performed using Discover S-class produced byCEM Corporation, or Initiator produced by Biotage.

LCMS spectra were measured using an Acquity SQD (quadrupole) produced byWaters Corporation under the following conditions.

Column: YMC-Triart C18, 2.0×50 mm, 1.9 μm (produced by YMC)MS detection: ESI positiveUV detection: 254 and 210 nmColumn flow rate: 0.5 mL/minMobile phase: Water/acetonitrile (0.1% formic acid)Injection volume: 1 μL

Gradient (Table 1) Time (min) Water (%) Acetonitrile (%) 0 95 5 0.1 95 52.1 5 95 3.0 STOP

Preparative reversed-phase HPLC purification was performed using apreparative separation system available from Waters Corporation.

Column: Connected YMC-Actus Triart C18, 20×50 mm, 5 μm

(produced by YMC) and YMC-Actus Triart C18, 20×10 mm, 5 μm(produced by YMC)UV detection: 254 nmMS detection: ESI positiveColumn flow rate: 25 mL/minMobile phase: Water/acetonitrile (0.1% formic acid)Injection volume: 0.1 to 0.5 mL

Abbreviations s: Singlet d: Doublet t: Triplet q: Quartet m: Multipletbrs: Broad Singlet brm: Broad Multiplet dd: Double Doublet dt: DoubleTriplet dq: Double Quartet ddd: Double Double Doublet

DMSO-d₆: Deuterated dimethyl sulfoxideCDCl₃: Deuterated chloroformCD₃OD: Deuterated methanolPdCl₂ (dppf) CH₂Cl₂: 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complexn-butyllithium: normal butyl lithium

Example 14-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of[(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol

(2R,3R,4S,5R)-2-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(15 g, 34.8 mmol) was suspended at room temperature in acetone (120 mL)and 2,2-dimethoxypropane (24.4 mL). Thereafter, boron trifluoridediethyl etherate (27.8 mL, 6.3 eq) was added thereto dropwise in an icebath with stirring so as to keep the internal temperature at 10° C. orlower. The obtained mixture was stirred for 75 minutes in an ice bath,and a 5 M aqueous sodium hydroxide solution (60 mL) was then slowlyadded thereto dropwise so as to keep the internal temperature at 15° C.or lower. After acetone was distilled off under reduced pressure,chloroform and water were added thereto, followed by stirring for about5 minutes. The reaction solution was filtered through a celite bed toremove the generated insoluble matter. Thereafter, the aqueous layer wasseparated and extracted twice with chloroform. All of the organic layerswere combined, washed with water and saturated saline, and dried oversodium sulfate, followed by distilling off the solvent. The brown oilresidue was suspended in hexane (50 mL), and stirred for 2 hours. Theformed solid was then collected by filtration, followed by drying,thereby obtaining the title compound (10.7 g, 71%) as a light-brownsolid.

¹H-NMR (CDCl₃) δ: 8.23 (1H, s), 7.12 (1H, s), 6.40 (1H, d, J=11.5 Hz),5.76-5.74 (2H, brs), 5.69 (1H, d, J=5.1 Hz), 5.24-5.22 (1H, m),5.10-5.08 (1H, m), 4.49 (1H, s), 3.97-3.94 (1H, m), 3.78 (1H, t, J=11.5Hz), 1.63 (3H, s), 1.36 (3H, s). LCMS (ESI) m/z 433 [M+H]⁺

Step 2: Synthesis of7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[(3aR,4R,6R,6aR)-4-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(3.2 g, 7.4 mmol) and phthalimide (2.18 g, 14.8 mmol) were dissolved intetrahydrofuran (30 mL), and triphenylphosphine (2.9 g, 11.1 mmol) wasadded thereto with stirring under ice-cooling. After triphenylphosphinewas dissolved, diisopropyl azodicarboxylate (2.2 mL, 11.1 mmol) wasadded thereto dropwise with stirring under ice-cooling. After thereaction solution was stirred for 1.5 h under ice-cooling, the reactionsolution was distilled off under reduced pressure, and ethanol (30 mL),water (9 mL), and hydrazine monohydrate (1.2 mL, 24.7 mmol) were addedat room temperature to the residue. After being stirred under refluxovernight, the reaction solution was distilled off under reducedpressure. The residue was partitioned between ethyl acetate andsaturated sodium bicarbonate solution. Then, the aqueous layer wasseparated and extracted with ethyl acetate. All of the organic layerswere combined and dried over sodium sulfate, followed by distilling offthe solvent. The residue was then purified by basic silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the title compound (3.23 g, quantitative) as a yellow solid.

¹H-NMR (CDCl₃) δ: 8.28 (1H, s), 7.19 (1H, s), 6.13 (1H, d, J=3.2 Hz),5.65-5.63 (2H, brs), 5.23 (1H, dd, J=6.7, 3.2 Hz), 4.93 (1H, dd, J=6.7,4.0 Hz), 4.18-4.14 (1H, m), 3.04 (1H, dd, J=13.4, 4.3 Hz), 2.93 (1H, dd,J=13.4, 5.9 Hz), 1.61 (3H, s), 1.37 (3H, s). LCMS (ESI) m/z 432 [M+H]⁺

Step 3: Synthesis of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate

7-((3aR,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(3.23 g) was dissolved in chloroform (40 mL), and1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido:1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: OrganicLetters, 2012, 10, 2626-2629) (6.2 g, 14.1 mmol) was added thereto atroom temperature. After the reaction solution was stirred for 2 hours atroom temperature, the precipitate was filtered off and washed withchloroform. After the filtrate was concentrated, the residue waspurified by silica gel column chromatography (developing solvent:chloroform/methanol), thereby obtaining the title compound (4.0 g, 88%)as a milky-white solid.

¹H-NMR (CDCl₃) δ: 9.27-9.25 (1H, brs), 8.50 (1H, s), 7.08 (1H, s),6.04-6.02 (2H, brs), 5.65 (1H, d, J=4.7 Hz), 5.28 (1H, dd, J=6.3, 4.7Hz), 5.07 (1H, dd, J=6.3, 2.2 Hz), 4.50 (1H, d, J=2.2 Hz), 3.63-3.49(2H, m), 1.61 (3H, s), 1.44 (9H, s), 1.35 (3H, s). LCMS (ESI) m/z 611[M+H]⁺

Step 4: Synthesis of Example Compound 1

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (20 mg, 0.033 mmol), 2-ethynyl-1,3-difluorobenzene (9.0 mg,0.066 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg,0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), anddiisopropylethylamine (0.011 mL, 0.066 mmol) were suspended intetrahydrofuran (0.20 mL). After the reaction solution was stirred at70° C. for 2 hours, a mixed solution (0.60 mL) of trifluoroaceticacid/water=4/1 was added thereto at room temperature, followed bystirring at room temperature overnight. After the solvent was distilledoff, the residue was purified by basic silica gel column chromatography(developing solvent: methanol/chloroform), thereby obtaining the titlecompound (14 mg, 91%) as a yellow powder.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 7.68 (1H, s), 7.45-7.37 (1H, m),7.10-7.04 (2H, m), 5.86 (1H, d, J=7.3 Hz), 4.86-4.81 (1H, m), 4.31-4.29(1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 481 [M+H]⁺

Step 5: Synthesis of4-amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidinehydrochloride

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2,6-difluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (8.05 g, 12.9 mmol) was dissolved in acetonitrile(120 mL), and concentrated hydrochloric acid (10.8 mL, 129 mmol) wasadded thereto at room temperature. After the mixture was stirred at roomtemperature for 6 hours, acetonitrile (80 mL) was added thereto,followed by stirring at room temperature overnight. The precipitate wascollected by filtration and washed with acetonitrile (80 mL), followedby drying, thereby obtaining the title compound hydrochloride (5.93 g,88%) as a white solid.

¹H-NMR (DMSO-D₆) δ: 8.42 (1H, s), 8.25 (1H, s), 7.55 (1H, tt, J=8.1, 7.7Hz), 7.28 (2H, dd, J=8.4, 8.1 Hz), 7.02 (1H, brs), 6.61 (1H, brs), 6.03(1H, d, J=6.6 Hz), 4.48 (1H, dd, J=6.6, 5.1 Hz), 4.12-4.10 (1H, m),4.06-4.03 (1H, m), 3.22 (1H, dd, J=13.9, 5.5 Hz), 3.12 (1H, dd, J=13.2,5.5 Hz). LCMS (ESI) m/z 481 [M+H]⁺.

Example 24-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(o-tolyl)thiazole

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (300 mg, 0.491 mmol), 1,1′-bis (diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (40.1 mg,0.049 mmol), and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole (295mg, 0.982 mmol) were suspended in a 2 M aqueous sodium carbonatesolution (1.23 mL) and dimethoxyethane (5 mL), followed by stirring at70° C. for 17 hours. The reaction solution was partitioned between ethylacetate and water, and the organic layer was washed with water andconcentrated. The residue was dissolved in acetonitrile (1 mL),trifluoroacetic acid (0.5 mL), and water (0.1 mL), followed by stirringat room temperature overnight. After the reaction liquid wasconcentrated, the residue was purified by basic silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the target product (110 mg, 43%) as a yellowish white solid.

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, s), 8.08 (1H, s), 8.06 (1H, s), 7.70 (1H,d, J=7.3 Hz), 7.46-7.35 (3H, m), 6.60 (2H, s), 5.97 (1H, d, J=6.6 Hz),5.40 (1H, d, J=6.6 Hz), 5.20 (1H, d, J=4.8 Hz), 4.60 (1H, dt, J=6.6, 5.5Hz), 4.14-4.11 (1H, m), 4.08-4.04 (1H, m), 2.53 (3H, s). LCMS (ESI) m/z518 [M+H]⁺.

Example 34-Amino-5-[2-(4-benzyloxyphenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-(benzyloxy)-4-ethynylbenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CDCl₃) δ: 8.29 (1H, s), 7.44-7.27 (8H, m), 6.96 (2H, d, J=8.8Hz), 5.69 (1H, d, J=6.8 Hz), 5.10 (2H, s), 4.87-4.84 (1H, m), 4.36-4.33(2H, m), 3.46-3.40 (4H, m). LCMS (ESI) m/z 551 [M+H]⁺.

Example 44-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[5-(2-pyridyl)-2-thienyl]ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that2-(5-ethynylthiophen-2-yl)pyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.49 (1H, d, J=5.1 Hz), 8.25 (1H, s), 7.84-7.82 (2H,m), 7.64 (1H, s), 7.64 (1H, d, J=4.1 Hz), 7.35 (1H, d, J=4.1 Hz),7.30-7.27 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.87-4.84 (1H, m), 4.32-4.30(1H, m), 4.28-4.25 (1H, m), 3.39-3.30 (2H, m). LCMS (ESI) m/z 528[M+H]⁺.

Example 54-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(2-methoxyphenyl)thiazole

The title compound was obtained as in Example 2, except that2-(2-methoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazolewas used in place of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole.

¹H-NMR (CD₃OD) δ: 8.20 (1H, s), 8.17 (1H, dd, J=7.7, 1.8 Hz), 7.88 (1H,s), 7.84 (1H, s), 7.49 (1H, dt, J=1.1, 8.8 Hz), 7.24 (1H, d, J=8.8 Hz),7.15 (1H, t, J=7.7 Hz), 5.98 (1H, d, J=6.6 Hz), 4.84-4.80 (1H, m), 4.36(1H, dd, J=5.5, 2.9 Hz), 4.29-4.26 (1H, m), 4.08 (3H, s), 3.47-3.37 (2H,m). LCMS (ESI) m/z 534 [M+H]⁺.

Example 64-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynylnaphthalene was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.36 (1H, d, J=8.0 Hz), 8.26 (1H, s), 7.93-7.90 (2H,m), 7.77 (1H, d, J=7.6 Hz), 7.73 (1H, s), 7.64-7.47 (3H, m), 5.90 (1H,d, J=6.8 Hz), 4.87-4.84 (1H, m), 4.34-4.32 (1H, m), 4.30-4.25 (1H, m),3.39-3.30 (2H, m). LCMS (ESI) m/z 495 [M+H]⁺.

Example 74-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-(3-phenylprop-1-ynyl)pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except thatprop-2-yn-1-yl benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.18 (1H, s), 7.43 (1H, s), 7.40 (2H, d, J=7.6 Hz),7.33 (2H, dd, J=7.6, 7.3 Hz), 7.24 (1H, t, J=7.3 Hz), 5.80 (1H, d, J=6.8Hz), 4.87-4.80 (1H, m), 4.30-4.25 (1H, m), 4.24-4.20 (1H, m), 3.88 (2H,s), 3.39-3.30 (2H, m). LCMS (ESI) m/z 459 [M+H]⁺.

Example 84-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

The title compound was obtained as in step 4 of Example 1, except that4-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.83 (1H, d, J=4.4 Hz), 8.40 (1H, d, J=9.5 Hz), 8.28(1H, s), 8.06 (1H, d, J=8.0 Hz), 7.91 (1H, s), 7.84 (1H, dd, J=8.8, 8.0Hz), 7.76-7.73 (2H, m), 5.93 (1H, d, J=6.6 Hz), 4.87-4.80 (1H, m),4.35-4.30 (1H, m), 4.29-4.26 (1H, m), 3.40-3.30 (2H, m). LCMS (ESI) m/z496 [M+H]⁺.

Example 94-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(phenoxymethyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-4-(phenoxymethyl)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 7.61 (1H, s), 7.57 (2H, d, J=8.3 Hz),7.49 (2H, d, J=8.3 Hz), 7.28 (2H, dd, J=8.0, 7.8 Hz), 7.00 (2H, d, J=7.8Hz), 6.94 (1H, t, J=8.0 Hz), 5.86 (1H, d, J=6.8 Hz), 5.12 (2H, s),4.85-4.75 (1H, m), 4.35-4.30 (1H, m), 4.28-4.25 (1H, m), 3.40-3.30 (2H,m). LCMS (ESI) m/z 551 [M+H]⁺.

Example 104-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-phenylcyclopropyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that(1-ethynylcyclopropyl)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.21 (1H, s), 7.46 (1H, s), 7.43-7.40 (2H, m), 7.32(2H, d, J=8.0 Hz), 7.23-7.19 (1H, m), 5.82 (1H, d, J=6.8 Hz), 4.82-4.79(1H, m), 4.30-4.28 (1H, m), 4.25-4.21 (1H, m), 3.37-3.34 (2H, m),1.54-1.50 (2H, m), 1.40-1.37 (2H, m). LCMS (ESI) m/z 485 [M+H]⁺.

Example 111-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]isoquinoline

The title compound was obtained as in step 4 of Example 1, except that1-ethynylisoquinoline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.56 (1H, d, J=8.0 Hz), 8.45 (1H, d, J=8.0 Hz), 8.23(1H, s), 8.19 (1H, s), 8.07 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.0 Hz),7.88-7.78 (2H, m), 7.38-7.34 (1H, brs), 6.64 (2H, s), 5.99 (1H, d, J=6.8Hz), 5.48-5.46 (1H, brs), 5.29-5.25 (1H, brs), 4.63-4.59 (1H, m),4.15-4.11 (1H, m), 4.10-4.06 (1H, m), 3.25-3.21 (1H, m), 3.18-3.12 (1H,m). LCMS (ESI) m/z 496 [M+H]⁺.

Example 124-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-phenyl-oxazol

The title compound was obtained as in Example 2, except that2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol was usedin place of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole.

¹H-NMR (CD₃OD) δ: 8.28 (1H, s), 8.07-8.00 (2H, m), 7.93 (1H, s),7.51-7.49 (3H, m), 7.48 (1H, s), 6.05 (1H, d, J=6.3 Hz), 4.77-4.71 (2H,m), 4.33 (1H, dd, J=5.4, 3.2 Hz), 4.26-4.22 (1H, m), 3.45-3.35 (2H, m).LCMS (ESI) m/z 488 [M+H]⁺.

Example 135-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

The title compound was obtained as in step 4 of Example 1, except that5-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.91 (1H, dd, J=4.4, 1.7 Hz), 8.84-8.78 (1H, m), 8.26(1H, s), 8.04 (1H, d, J=8.5 Hz), 7.89 (1H, dd, J=7.9, 1.1 Hz), 7.81 (1H,s), 7.80-7.76 (1H, m), 7.67 (1H, dd, J=8.5, 4.4 Hz), 5.92 (1H, d, J=6.8Hz), 4.87-4.82 (1H, m), 4.35-4.33 (1H, m), 4.29-4.26 (1H, m), 3.45-3.36(2H, m). LCMS (ESI) m/z 496 [M+H]⁺.

Example 144-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-(trifluoromethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2-(trifluoromethoxy)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.26 (1H, s), 7.68-7.62 (1H, m), 7.65 (1H, s),7.50-7.46 (1H, m), 7.42-7.38 (2H, m), 5.86 (1H, d, J=7.1 Hz), 4.86-4.81(1H, m), 4.31-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS(ESI) m/z 529 [M+H]⁺.

Example 154-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methoxy-1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2-methoxynaphthalene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.89-7.80 (2H, m), 7.66-7.57 (1H, m),7.64 (1H, s), 7.58-7.54 (1H, m), 7.42-7.36 (2H, m), 5.90 (1H, d, J=8.0Hz), 4.83-4.81 (1H, m), 4.37-4.33 (1H, m), 4.27-4.25 (1H, m), 4.06 (3H,s), 3.40-3.35 (2H, m). LCMS (ESI) m/z 525 [M+H]⁺.

Example 164-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2,6-dimethoxyphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-1,3-dimethoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.50 (1H, s), 7.28 (1H, t, J=8.5 Hz),6.69 (2H, d, J=8.5 Hz), 5.86 (1H, d, J=6.8 Hz), 4.83-4.81 (1H, m),4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.91 (6H, s), 3.40-3.35 (2H, m).LCMS (ESI) m/z 505 [M+H]⁺.

Example 178-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

The title compound was obtained as in step 4 of Example 1, except that8-ethynylquinoline was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.99 (1H, dd, 4.1, 1.7 Hz), 8.33 (1H, dd, 8.5, 1.7Hz), 8.22 (1H, s), 7.91 (1H, s), 7.90-7.82 (2H, m), 7.58-7.52 (2H, m),5.86 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25(1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 496 [M+H]⁺.

Example 184-Amino-5-[2-[2-(difluoromethoxy)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-(difluoromethoxy)-2-ethynylbenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.62 (1H, s), 7.58 (1H, d, J=7.8, 1.7Hz), 7.43-7.39 (1H, m), 7.28-7.23 (2H, m), 7.01 (1H, t, J=7.2 Hz), 5.86(1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H,m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 511 [M+H]⁺.

Example 194-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1H-pyrazolo[4,3-b]pyridin-5-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that5-ethynyl-1H-pyrazolo[4,3-b]pyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 8.23 (1H, s), 8.06 (1H, d, J=8.8 Hz),7.75 (1H, s), 7.64 (1H, d, J=8.8 Hz), 5.89 (1H, d, J=6.8 Hz), 4.87-4.85(1H, m), 4.34-4.30 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS(ESI) m/z 486 [M+H]⁺.

Example 204-Amino-5-[2-(4-amino-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3-fluoroaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.48 (1H, s), 7.21-7.17 (1H, m),6.46-6.41 (2H, m), 5.84 (1H, d, J=6.8 Hz), 4.87-4.85 (1H, m), 4.32-4.28(1H, m), 4.27-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 478[M+H]⁺.

Example 214-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-(2-indan-1-ylethynyl)pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2,3-dihydro-1H-indene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.19 (1H, s), 7.42 (1H, s), 7.42-7.38 (1H, m),7.26-7.18 (3H, m), 5.81 (1H, d, J=7.1 Hz), 4.84-4.79 (1H, m), 4.30-4.18(3H, m), 3.40-3.35 (2H, m), 3.04-2.91 (2H, m), 2.62-2.54 (1H, m),2.19-2.11 (1H, m). LCMS (ESI) m/z 485 [M+H]⁺.

Example 224-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methylsulfonylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2-(methylsulfonyl)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 8.07 (1H, dd, J=7.7, 1.3 Hz), 7.79 (1H,dd, J=7.7, 1.3 Hz), 7.77 (1H, s), 7.75-7.70 (1H, m), 7.62-7.57 (1H, m),5.89 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.28-4.24(1H, m), 3.40-3.35 (2H, m), 3.30 (3H, s). LCMS (ESI) m/z 523 [M+H]⁺.

Example 234-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]morpholineStep 1: Synthesis of 4-(4-ethynyl-3,5-difluorophenyl)morpholine

2-Ethynyl-1,3,5-trifluorobenzene (52 mg, 0.33 mmol) and cesium carbonate(163 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (0.50 mL).Morpholine (0.044 mL, 0.50 mmol) was added thereto at room temperature,followed by stirring at 80° C. overnight. After the resulting mixturewas air-cooled to room temperature, ethyl acetate (2.0 mL) and asaturated aqueous ammonium chloride solution (1.0 mL) were sequentiallyadded thereto, and the mixture was partitioned into an aqueous layer andan organic layer. The organic layer was then sequentially washed withwater and saturated saline, and dried over anhydrous sodium sulfate,followed by distilling off the solvent. The residue was purified bysilica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining4-(4-ethynyl-3,5-difluorophenyl)morpholine (40 mg, 54%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 6.37 (2H, d, J=10.7 Hz), 3.83 (4H, dd, J=5.7, 4.2 Hz),3.40 (1H, s), 3.19 (4H, dd, J=5.7, 4.2 Hz). LCMS (ESI) m/z 224 [M+H]⁺

Step 2: Synthesis of Example Compound 23

The title compound was obtained as in step 4 of Example 1, except that4-(4-ethynyl-3,5-difluorophenyl)morpholine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.56 (1H, s), 6.63 (2H, d, J=11.5 Hz),5.85 (1H, d, J=7.1 Hz), 4.85-4.79 (1H, m), 4.30 (1H, dd, J=5.6, 2.4 Hz),4.27-4.23 (1H, m), 3.80 (4H, t, J=4.9 Hz), 3.42-3.32 (2H, m), 3.27-3.22(4H, m). LCMS (ESI) m/z 566 [M+H]⁺.

Example 244-Amino-5-[2-(4-amino-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3,5-difluoroaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.52 (1H, s), 6.26 (2H, d, J=10.2 Hz),5.85 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23(1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m/z 496 [M+H]⁺.

Example 254-Amino-5-[2-[2,6-difluoro-4-(methylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3,5-difluoro-N-methylaniline

The title compound was obtained as in step 1 of Example 23, except thatmethylamine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.11 (2H, d, J=10.6 Hz), 4.22-4.14 (1H, brm), 3.39(1H, s), 2.84 (3H, s). LRMS (ESI) m/z 168 [M+H]⁺

Step 2: Synthesis of Example Compound 25

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3,5-difluoro-N-methylaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 8.18 (1H, brs), 8.03 (1H, dd, J=7.7, 1.1Hz), 7.53 (1H, s), 7.48 (1H, t, J=7.7 Hz), 6.22 (2H, d, J=11.0 Hz), 5.86(1H, d, J=7.0 Hz), 4.86-4.81 (1H, m), 4.32 (1H, dd, J=5.5, 2.2 Hz),4.27-4.25 (1H, m), 3.43-3.34 (2H, m), 2.79 (3H, s). LCMS (ESI) m/z 510[M+H]⁺.

Example 264-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(ethylamino)-2,6-difluoro-phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of N-ethyl-4-ethynyl-3,5-difluoroaniline

The title compound was obtained as in step 1 of Example 23, except thatethylamine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.10 (2H, d, J=10.3 Hz), 4.07-4.00 (1H, brm), 3.38(1H, s), 3.18-3.11 (2H, m), 1.27 (5H, t, J=7.3 Hz). LRMS (ESI) m/z 182[M+H]⁺

Step 2: Synthesis of Example Compound 26

The title compound was obtained as in step 4 of Example 1, except thatN-ethyl-4-ethynyl-3,5-difluoroaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 8.07-8.00 (1H, m), 7.59-7.45 (1H, m),7.57 (1H, s), 6.23 (2H, d, J=11.0 Hz), 5.89 (1H, d, J=7.0 Hz), 4.80 (1H,dd, J=7.0, 5.5 Hz), 4.32 (1H, dd, J=5.5, 2.6 Hz), 4.26 (1H, ddd, J=4.0,3.7, 2.6 Hz), 3.41 (1H, dd, J=13.2, 3.7 Hz), 3.36 (1H, dd, J=13.2, 4.0Hz), 3.13 (2H, q, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 524[M+H]⁺

Example 274-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[3-(isopropylamino)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that3-ethynyl-N-isopropylaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.55 (1H, s), 7.11 (1H, t, J=8.3 Hz),6.79-6.76 (2H, m), 6.67-6.65 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.84-4.79(1H, m), 4.31 (1H, dd, J=5.6, 2.4 Hz), 4.25 (1H, q, J=3.2 Hz), 3.67-3.54(1H, m), 3.39-3.35 (2H, m), 1.20 (6H, d, J=6.3 Hz). LCMS (ESI) m/z 502[M+H]⁺.

Example 284-Amino-5-[2-(5-amino-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that3-ethynyl-4-fluoroaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.90 (1H, s), 7.38-7.33 (1H, m), 6.99(1H, t, J=9.3 Hz), 6.70 (1H, dd, J=6.1, 2.9 Hz), 6.62-6.56 (3H, m), 5.92(1H, d, J=7.1 Hz), 5.40 (1H, d, J=6.3 Hz), 5.23 (1H, d, J=4.4 Hz), 5.16(2H, s), 4.57 (1H, dd, J=12.1, 6.7 Hz), 4.12-4.08 (1H, m), 4.07-4.03(1H, m), 3.24-3.08 (2H, m). LCMS (ESI) m/z 478 [M+H]⁺.

Example 294-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of(3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine

The title compound was obtained as in step 1 of Example 23, except that(R)-3-fluoropyrrolidine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.07 (2H, d, J=10.3 Hz), 5.38 (1H, d, J=52.8 Hz),3.59-3.38 (5H, m), 2.47-2.36 (1H, m), 2.27-2.06 (1H, m). LCMS (ESI) m/z226 [M+H]⁺

Step 2: Synthesis of Example Compound 29

The title compound was obtained as in step 4 of Example 1, except that(3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used inplace of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, s), 7.84 (1H, s), 7.35-7.30 (1H, m), 6.58(2H, s), 6.42 (2H, d, J=11.2 Hz), 5.91 (1H, d, J=7.1 Hz), 5.45 (1H, d,J=52.7 Hz), 5.37 (1H, d, J=6.3 Hz), 5.20 (1H, d, J=4.4 Hz), 4.56 (1H,dd, J=12.1, 6.7 Hz), 4.11-4.07 (1H, m), 4.06-4.01 (1H, m), 3.61-3.45(3H, m), 3.41-3.33 (1H, m), 3.24-3.16 (1H, m), 3.14-3.06 (1H, m),2.30-2.10 (2H, m). LCMS (ESI) m/z 568 [M+H]⁺.

Example 304-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of(3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol

The title compound was obtained as in step 1 of Example 23, except that(R)-pyrrolidin-3-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.02 (2H, d, J=10.5 Hz), 4.63-4.60 (1H, m), 3.50-3.43(2H, m), 3.40-3.38 (1H, m), 3.33 (1H, dt, J=3.3, 9.0 Hz), 3.22 (1H, d,J=10.7 Hz), 2.22-2.11 (1H, m), 2.11-2.06 (1H, m). LCMS (ESI) m/z 224[M+H]⁺

Step 2: Synthesis of Example Compound 30

The title compound was obtained as in step 4 of Example 1, except that(3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in placeof 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.85 (1H, s), 7.36 (1H, dd, J=7.7, 4.8Hz), 6.60 (2H, s), 6.35 (2H, d, J=11.0 Hz), 5.91 (1H, d, J=7.0 Hz), 5.39(1H, d, J=6.2 Hz), 5.23 (1H, d, J=4.4 Hz), 5.06 (1H, d, J=3.7 Hz),4.60-4.55 (1H, m), 4.42-4.37 (1H, m), 4.11-4.07 (1H, m), 4.06-4.02 (1H,m), 3.45-3.37 (2H, m), 3.24-3.18 (1H, m), 3.16-3.09 (2H, m), 2.07-1.99(1H, m), 1.94-1.86 (1H, m). LCMS (ESI) m/z 566.3 [M+H]⁺.

Example 314-Amino-5-[3-(2,6-difluorophenyl)prop-1-ynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1,3-difluoro-2-(prop-2-yn-1-yl)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.20 (1H, s), 7.40 (1H, s), 7.36-7.30 (1H, m),7.04-6.99 (2H, m), 5.79 (1H, d, J=6.8 Hz), 4.80-4.69 (1H, m), 4.28-4.25(1H, m), 4.22-4.20 (1H, m), 3.88 (2H, s), 3.39-3.32 (2H, m). LCMS (ESI)m/z 495 [M+H]⁺.

Example 324-Amino-5-[2-[2,6-difluoro-4-(2-hydroxyethylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

2-((4-Ethynyl-3,5-difluorophenyl)amino)ethanol was obtained as in step 1of Example 23, except that 2-aminoethanol was used in place ofmorpholine, and the title compound was then obtained as in step 4 ofExample 1, except that the thus-obtained2-((4-ethynyl-3,5-difluorophenyl)amino)ethanol was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, s), 7.91 (1H, s), 7.38 (1H, s), 7.03 (2H,t, J=9.5 Hz), 6.61 (2H, brs), 5.93 (1H, d, J=6.6 Hz), 5.47-5.36 (1H, m),5.34-5.18 (1H, m), 4.60 (1H, t, J=10.0 Hz), 4.13-4.08 (1H, m), 4.08-4.04(1H, m), 3.26-3.19 (1H, m), 3.16-3.08 (1H, m), 2.55 (2H, s). LCMS (ESI)m/z 540.3 [M+H]⁺.

Example 334-Amino-5-[2-[2,6-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidin-2-one

The title compound was obtained as in step 1 of Example 23, except thatpyrrolidin-2-one was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 7.35 (2H, d, J=10.0 Hz), 3.82 (2H, t, J=7.2 Hz), 3.47(1H, s), 2.65 (2H, t, J=8.2 Hz), 2.23-2.15 (2H, m). LCMS (ESI) m/z 222[M+H]⁺

Step 2: Synthesis of Example Compound 33

The title compound was obtained as in step 4 of Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)pyrrolidin-2-one was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.97 (1H, s), 7.64 (2H, d, J=10.5 Hz),7.33-7.30 (1H, brs), 6.58 (2H, s), 5.92 (1H, d, J=7.3 Hz), 5.38 (1H, d,J=6.8 Hz), 5.21 (1H, d, J=4.1 Hz), 4.60-4.54 (1H, m), 4.08-4.07 (1H, m),4.05-4.02 (1H, m), 3.84 (2H, t, J=7.2 Hz), 3.27-3.18 (1H, m), 3.15-3.08(1H, m), 2.56 (2H, t, J=8.2 Hz), 2.10-2.02 (2H, m). LCMS (ESI) m/z 564[M+H]⁺.

Example 344-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholineStep 1: Synthesis of 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine

4-(4-ethynyl-3,5-difluorophenyl)morpholine (100 mg, 0.448 mmol) wasdissolved in ethanol (3 mL). Sodium ethoxide (a 21 wt % ethanolsolution, 0.168 mL, 0.448 mmol) was added thereto, followed by stirringfor 0.5 hours in a sealed container at 160° C. After the resultingmixture was air-cooled to room temperature, ethyl acetate (5.0 mL) and asaturated ammonium chloride solution (2.0 mL) were sequentially addedthereto, and the mixture was partitioned into an aqueous layer and anorganic layer. The organic layer was then sequentially washed with waterand saturated saline, and dried over anhydrous sodium sulfate, followedby distilling off the solvent. The residue was purified by silica gelcolumn chromatography (developing solvent: hexane/ethyl acetate),thereby obtaining 4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine (60mg, 54%) as a green solid.

¹H-NMR (CDCl₃) δ: 6.20 (1H, dd, J=12.1, 2.2 Hz), 6.13 (1H, s), 4.12-4.07(2H, m), 3.85-3.82 (4H, m), 3.41 (1H, s), 3.20-3.15 (4H, m), 1.46 (3H,t, J=7.1 Hz). LCMS (ESI) m/z 250 [M+H]⁺

Step 2: Synthesis of Example Compound 34

The title compound was obtained as in Example 1, except that4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.77 (1H, s), 7.41-7.36 (1H, m), 6.60(2H, s), 6.48 (1H, d, J=13.6 Hz), 6.42 (1H, s), 5.90 (1H, d, J=7.0 Hz),5.37 (1H, d, J=6.6 Hz), 5.21 (1H, d, J=4.4 Hz), 4.60-4.55 (1H, m), 4.20(2H, q, J=7.0 Hz), 4.12-4.07 (1H, m), 4.06-4.02 (1H, m), 3.74-3.69 (4H,m), 3.27-3.05 (6H, m), 1.36 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 592[M+H]⁺.

Example 354-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-4,6-difluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-ethoxy-2-ethynyl-3,5-difluorobenzene

The title compound was obtained as in step 1 of Example 34, except that2-ethynyl-1,3,5-trifluorobenzene was used in place of4-(4-ethynyl-3,5-difluorophenyl)morpholine.

¹H-NMR (CDCl₃) δ: 6.48-6.39 (2H, m), 4.09 (2H, q, J=7.0 Hz), 3.45 (1H,s), 1.47 (3H, t, J=7.0 Hz).

Step 2: Synthesis of Example Compound 35

The title compound was obtained as in Example 1, except that1-ethoxy-2-ethynyl-3,5-difluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.90 (1H, s), 7.36 (1H, s), 7.02-6.97(2H, m), 6.61-6.58 (2H, m), 5.92 (1H, d, J=7.1 Hz), 5.41-5.36 (1H, m),5.24-5.21 (1H, m), 4.61-4.55 (1H, m), 4.24 (2H, q, J=7.0 Hz), 4.11-4.08(1H, m), 4.07-4.03 (1H, m), 3.25-3.07 (2H, m), 1.38 (3H, t, J=7.0 Hz).LCMS (ESI) m/z 525 [M+H]⁺.

Example 364-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[3-(2-fluorophenyl)prop-1-ynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in Example 1, except that1-fluoro-2-(prop-2-yn-1-yl)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.20 (1H, s), 7.54 (1H, t, J=8.0 Hz), 7.45 (1H, s),7.33-7.25 (1H, m), 7.20-7.16 (1H, m), 7.13-7.08 (1H, m), 5.82 (1H, d,J=6.8 Hz), 4.80-4.77 (1H, m), 4.30-4.28 (1H, m), 4.24-4.23 (1H, m), 3.90(2H, s), 3.40-3.31 (2H, m). LCMS (ESI) m/z 477 [M+H]⁺.

Example 374-[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]thiomorpholineStep 1: Synthesis of 4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine

The title compound was obtained as in step 1 of Example 23, except thatthiomorpholine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.32 (2H, d, J=11.0 Hz), 3.69-3.66 (4H, m), 3.38 (1H,s), 2.69-2.66 (4H, m). LCMS (ESI) m/z 240 [M+H]⁺

Step 2: Synthesis of Example Compound 37

The title compound was obtained as in Example 1, except that4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.87 (1H, s), 7.36-7.32 (1H, m), 6.78(2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.46-5.32 (1H,m), 5.30-5.16 (1H, m), 4.59-4.55 (1H, m), 4.11-4.07 (1H, m), 4.06-4.02(1H, m), 3.78-3.72 (4H, m), 3.24-3.06 (2H, m), 2.63-2.58 (4H, m). LCMS(ESI) m/z 582 [M+H]⁺.

Example 384-Amino-5-[2-[2,6-difluoro-4-(3-hydroxy-1-piperidyl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol

The title compound was obtained as in step 1 of Example 23, except thatpiperidin-3-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.39 (2H, dt, J=17.2, 3.2 Hz), 3.91-3.83 (1H, m), 3.49(1H, dd, J=12.7, 3.4 Hz), 3.38 (1H, s), 3.31-3.28 (1H, m), 3.12-3.00(2H, m), 1.98-1.82 (3H, m), 1.68-1.56 (2H, m). LCMS (ESI) m/z 238 [M+H]⁺

Step 2: Synthesis of Example Compound 38

The title compound was obtained as in Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72(2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d,J=6.2 Hz), 5.22 (1H, d, J=3.3 Hz), 4.88-4.83 (1H, m), 4.60-4.54 (1H, m),4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.68-3.51 (3H, m), 3.25-3.17 (1H,m), 3.15-3.07 (1H, m), 3.01-2.94 (1H, m), 2.84 (1H, dd, J=12.6, 8.6 Hz),1.89-1.83 (1H, m), 1.75-1.69 (1H, m), 1.48-1.34 (2H, m). LCMS (ESI) m/z580 [M+H]⁺.

Example 394-Amino-5-[2-[2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)azetidin-3-ol

The title compound was obtained as in step 1 of Example 23, except thatazetidin-3-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 5.90 (2H, dq, J=19.2, 3.4 Hz), 4.83-4.76 (1H, m), 4.17(2H, dd, J=8.4, 7.0 Hz), 3.75 (2H, dd, J=8.4, 4.2 Hz), 3.38 (1H, s),2.21 (1H, d, J=6.2 Hz). LCMS (ESI) m/z 210 [M+H]⁺

Step 2: Synthesis of Example Compound 39

The title compound was obtained as in Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)azetidin-3-ol was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.85 (1H, s), 7.37-7.32 (1H, m), 6.59(2H, s), 6.24 (2H, d, J=9.9 Hz), 5.91 (1H, d, J=7.0 Hz), 5.75 (1H, d,J=6.6 Hz), 5.38 (1H, d, J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.60-4.54(2H, m), 4.16-4.07 (3H, m), 4.06-4.02 (1H, m), 3.64 (2H, dd, J=8.6, 4.6Hz), 3.25-3.17 (1H, m), 3.14-3.05 (1H, m). LCMS (ESI) m/z 552 [M+H]⁺.

Example 404-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxy-1-piperidyl]phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of (3R)-1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol

The title compound was obtained as in step 1 of Example 23, except that(R)-piperidin-3-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.39 (2H, d, J=11.0 Hz), 3.91-3.84 (1H, m), 3.49 (1H,dd, J=12.5, 3.3 Hz), 3.38 (1H, s), 3.33-3.27 (1H, m), 3.12-3.01 (2H, m),1.98-1.85 (2H, m), 1.80 (1H, d, J=6.2 Hz), 1.69-1.60 (1H, m). LCMS (ESI)m/z 238 [M+H]⁺

Step 2: Synthesis of Example Compound 40

The title compound was obtained as in Example 1, except that(3R)-1-(4-ethynyl-3,5-difluorophenyl)piperidin-3-ol was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.86 (1H, s), 7.36-7.32 (1H, m), 6.72(2H, d, J=12.1 Hz), 6.59 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d,J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.86 (1H, d, J=4.4 Hz), 4.57 (1H, dd,J=12.3, 6.8 Hz), 4.11-4.08 (1H, m), 4.06-4.03 (1H, m), 3.68-3.50 (3H,m), 3.23-3.18 (1H, m), 3.15-3.07 (1H, m), 3.01-2.94 (1H, m), 2.84 (1H,dd, J=12.6, 8.6 Hz), 1.89-1.83 (1H, m), 1.75-1.69 (1H, m), 1.47-1.37(2H, m). LCMS (ESI) m/z 580 [M+H]⁺.

Example 411-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]pyrrolidine-3-carboxylicacid Step 1: Synthesis of1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid

The title compound was obtained as in step 1 of Example 23, except thatpyrrolidine-3-carboxylic acid was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.06 (2H, d, J=10.3 Hz), 3.61-3.52 (2H, m), 3.46-3.25(4H, m), 2.38-2.33 (2H, m). LCMS (ESI) m/z 252 [M+H]⁺

Step 2: Synthesis of Example Compound 41

The title compound was obtained as in step 4 of Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid was usedin place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 12.59 (1H, s), 8.17 (1H, s), 7.85 (1H, s), 7.36-7.32(1H, m), 6.59 (2H, s), 6.39 (2H, d, J=11.0 Hz), 5.91 (1H, d, J=7.0 Hz),5.38 (1H, d, J=6.2 Hz), 5.22 (1H, d, J=4.4 Hz), 4.59-4.55 (1H, m),4.12-4.08 (1H, m), 4.06-4.02 (1H, m), 3.54-3.42 (2H, m), 3.24-3.07 (5H,m), 2.27-2.11 (2H, m). LCMS (ESI) m/z 594 [M+H]⁺.

Example 424-Amino-5-[2-[2,6-difluoro-4-(4-oxo-1-piperidyl)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-one

The title compound was obtained as in step 1 of Example 23, except thatpiperidin-4-one was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.40 (2H, d, J=11.0 Hz), 3.66 (4H, t, J=6.0 Hz), 3.41(1H, s), 2.57 (4H, t, J=6.0 Hz). LCMS (ESI) m/z 236 [M+H]⁺

Step 2: Synthesis of Example Compound 42

The title compound was obtained as in step 4 of Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-one was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.88 (1H, s), 7.37-7.32 (1H, m), 6.86(2H, d, J=11.7 Hz), 6.60 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.40 (1H, d,J=6.2 Hz), 5.24 (1H, d, J=4.0 Hz), 4.60-4.55 (1H, m), 4.11-4.08 (1H, m),4.06-4.03 (1H, m), 3.73 (4H, t, J=5.9 Hz), 3.25-3.18 (1H, m), 3.14-3.07(1H, m), 2.44 (4H, t, J=5.9 Hz). LCMS (ESI) m/z 578 [M+H]⁺.

Example 434-amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)azetidine

The title compound was obtained as in step 1 of Example 23, except thatazetidine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 5.86 (2H, d, J=9.5 Hz), 3.93-3.89 (4H, m), 3.37 (1H,s), 2.45-2.37 (2H, m). LCMS (ESI) m/z 194 [M+H]⁺

Step 2: Synthesis of Example Compound 43

The title compound was obtained as in step 4 of Example 1, except that1-(4-ethynyl-3,5-difluorophenyl)azetidine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.85 (1H, s), 7.36-7.33 (1H, m), 6.60(2H, s), 6.20 (2H, d, J=9.9 Hz), 5.91 (1H, d, J=7.0 Hz), 5.38 (1H, d,J=6.6 Hz), 5.22 (1H, d, J=4.4 Hz), 4.57 (1H, q, J=6.2 Hz), 4.11-4.07(1H, m), 4.05-4.03 (1H, m), 3.91 (4H, t, J=7.3 Hz), 3.25-3.17 (1H, m),3.14-3.07 (1H, m), 2.37-2.30 (2H, m). LCMS (ESI) m/z 536 [M+H]⁺.

Example 444-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that2-ethynylpyridine was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.90 (1H, s), 7.78 (1H, t, J=7.6 Hz),7.60 (1H, d, J=7.6 Hz), 7.33 (1H, dd, J=7.6, 5.1 Hz), 7.28 (1H, dd,J=7.6, 5.1 Hz), 6.53 (2H, s), 5.86 (1H, d, J=7.0 Hz), 4.52 (1H, dd,J=7.0, 5.7 Hz), 4.04 (1H, dd, J=5.1, 2.5 Hz), 4.01-3.97 (1H, brm),3.18-3.02 (2H, m). LCMS (ESI) m/z 446 [M+H]⁺.

Example 45 4-Amino-5-[2-(2-chlorophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-chloro-2-ethynylbenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.88 (1H, s), 7.63-7.52 (1H, m),7.54-7.53 (1H, m), 7.38-7.32 (2H, m), 7.27 (1H, dd, J=7.6, 5.1 Hz), 6.53(2H, s), 5.86 (1H, d, J=7.0 Hz), 4.51 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H,dd, J=5.1, 2.5 Hz), 4.00-3.97 (1H, brm), 3.19-3.02 (2H, m). LCMS (ESI)m/z 479 [M+H]⁺.

Example 464-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluorophenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.11 (1H, s), 7.86 (1H, s), 7.58 (1H, t, J=7.6 Hz),7.43-7.37 (1H, m), 7.30-7.26 (2H, m), 7.21 (1H, t, J=7.6 Hz), 6.52 (2H,s), 5.86 (1H, d, J=7.0 Hz), 4.51 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, t,J=2.5 Hz), 4.00-3.97 (1H, m), 3.17-3.02 (2H, m). LCMS (ESI) m/z 463[M+H]⁺.

Example 474-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methoxyphenyl)ethynylI]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that1-ethynyl-2-methoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04(1H, d, J=8.2 Hz), 6.92 (1H, t, J=7.6 Hz), 6.53 (2H, s), 5.84 (1H, d,J=7.0 Hz), 4.50 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, dd, J=5.1, 2.5 Hz),3.84-3.84 (1H, brm), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m/z 475[M+H]⁺.

Example 484-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(4-dimethylaminophenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-N,N-dimethylaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, s), 7.73 (1H, s), 7.36-7.29 (3H, m), 7.04(1H, d, J=8.2 Hz), 6.92 (1H, t, J=7.6 Hz), 6.53 (2H, s), 5.84 (1H, d,J=7.0 Hz), 4.50 (1H, dd, J=7.0, 5.1 Hz), 4.03 (1H, dd, J=5.1, 2.5 Hz),3.84-3.84 (1H, brm), 4.00 (3H, s), 3.21-3.01 (2H, m). LCMS (ESI) m/z 475[M+H]⁺.

Example 494-Amino-5-[2-(2-cyanophenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except that2-ethynylbenzonitrile was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.93 (1H, s), 7.87 (1H, d, J=7.5 Hz),7.74-7.68 (2H, m), 7.52 (1H, dt, J=1.4, 7.5 Hz), 7.29 (1H, m), 6.53 (2H,s), 5.87 (1H, d, J=6.8 Hz), 5.40 (1H, brs), 5.23 (1H, brs), 4.53 (1H, t,J=5.5 Hz), 4.04 (2H, dd, J=5.5, 2.7 Hz), 4.01-3.98 (2H, brm), 3.19-3.03(2H, m). LCMS (ESI) m/z 470 [M+H]⁺.

Example 504-Amino-5-(3-cyclohexylprop-1-ynyl)-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 4 of Example 1, except thatprop-2-yn-1-yl cyclohexane was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, s), 7.56 (1H, s), 7.27 (1H, dd, J=7.5, 4.1Hz), 6.51 (2H, s), 5.79 (1H, d, J=6.8 Hz), 4.46 (1H, dd, J=6.8, 5.5 Hz),4.01 (1H, dd, J=5.5, 2.1 Hz), 3.97-3.94 (1H, brm), 3.17-2.99 (2H, m),2.32 (2H, d, J=6.2 Hz), 1.76-1.72 (2H, brm), 1.65-1.60 (2H, brm),1.58-1.54 (1H, brm), 1.49-1.41 (1H, brm), 1.23-0.93 (5H, m). LCMS (ESI)m/z 465 [M+H]⁺.

Example 514-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-ethynyl-1-fluoro-3-methoxybenzene

2-Fluoro-6-methoxybenzaldehyde (2.0 g, 13 mmol) was dissolved inmethanol (20 mL). Then, potassium carbonate (3.6 g, 26 mmol) was addedthereto at room temperature, anddimethyl(1-diazo-2-oxopropyl)phosphonate (2.3 mL, 16 mmol) was addedthereto under ice-cooling, followed by stirring under ice-cooling for 1hour and at room temperature for another 1 hour. The reaction solutionwas partitioned with the addition of ethyl acetate, a saturated aqueoussodium hydrogen carbonate solution, and water, and the organic layer waswashed with saturated saline. After being dried over sodium sulfate, theresulting product was filtered and concentrated, and the residue waspurified by silica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining 2-ethynyl-1-fluoro-3-methoxybenzene(1.6 g, 11 mmol, 81%) as a reddish brown solid.

¹H-NMR (CDCl₃) δ: 7.31-7.22 (1H, m), 6.76-6.65 (2H, m), 3.92 (3H, s),3.53 (1H, s).

Step 2: Synthesis of Example Compound 51

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-1-fluoro-3-methoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.57 (1H, s), 7.37-7.30 (1H, m), 6.90(1H, d, J=8.5 Hz), 6.82-6.78 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.87-4.85(1H, m), 4.32-4.27 (1H, m), 4.26-4.24 (1H, m), 3.97 (3H, s), 3.40-3.35(2H, m). LCMS (ESI) m/z 493 [M+H]⁺.

Example 524-Amino-5-[2-(5-benzyloxy-2-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 5-(benzyloxy)-2-ethynylpyridine

The title compound was obtained as in step 1 of Example 51, except that5-(benzyloxy)picolinaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 8.36 (1H, d, J=2.9 Hz), 7.44-7.34 (5H, m), 7.20 (2H,dd, 8.8, 2.9 Hz), 5.13 (2H, s), 3.07 (1H, s). LCMS (ESI) m/z 210 [M+H]⁺

Step 2: Synthesis of Example Compound 52

The title compound was obtained as in step 4 of Example 1, except that5-(benzyloxy)-2-ethynylpyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.29 (1H, d, J=2.9 Hz), 8.22 (1H, s), 7.65 (1H, s),7.56 (1H, d, J=8.0 Hz), 7.50-7.30 (6H, m), 5.86 (1H, d, J=6.8 Hz), 5.20(2H, s), 4.85-4.75 (1H, m), 4.35-4.20 (2H, m), 3.40-3.30 (2H, m). LCMS(ESI) m/z 552 [M+H]⁺.

Example 534-Amino-5-[2-(4-benzyloxy-2-methoxy-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-(benzyloxy)-1-ethynyl-2-methoxybenzene

The title compound was obtained as in step 1 of Example 51, except that4-(benzyloxy)-2-methoxybenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.48-7.32 (6H, m), 6.50-6.55 (2H, m), 5.07 (2H, s),3.87 (3H, s), 3.24 (1H, s). LCMS (ESI) m/z 239 [M+H]⁺

Step 2: Synthesis of Example Compound 53

The title compound was obtained as in step 4 of Example 1, except that4-(benzyloxy)-1-ethynyl-2-methoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, s), 7.74 (1H, s), 7.46-7.32 (7H, m),6.78-6.76 (1H, brs), 6.67 (1H, d, J=8.0 Hz), 6.63-6.59 (2H, brs), 5.90(1H, d, J=6.3 Hz), 5.39 (1H, d, J=6.1 Hz), 5.23 (1H, d, J=4.1 Hz), 5.16(2H, s), 4.61-4.55 (1H, m), 4.12-4.08 (1H, m), 4.06-4.04 (1H, m), 3.89(3H, s), 3.26-3.15 (1H, m), 3.15-3.03 (1H, m). LCMS (ESI) m/z 581[M+H]⁺.

Example 544-Amino-5-[2-(2,6-difluoro-4-hydroxy-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3,5-difluorophenol

The title compound was obtained as in step 1 of Example 51, except that2,6-difluoro-4-hydroxybenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 6.43 (2H, d, J=8.0 Hz), 5.60-5.40 (1H, brs.), 3.42(1H, s).

Step 2: Synthesis of Example Compound 54

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3,5-difluorophenol was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.58 (1H, s), 6.48 (2H, d, J=9.5 Hz),5.86 (1H, d, J=6.8 Hz), 4.85-4.81 (1H, m), 4.33-4.29 (1H, m), 4.26-4.23(1H, m), 3.40-3.34 (2H, m). LCMS (ESI) m/z 497 [M+H]⁺.

Example 554-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-ethoxy-6-fluorobenzaldehyde

2-Fluoro-6-hydroxybenzaldehyde (50 g, 360 mmol) was dissolved inN,N-dimethylformamide (500 mL), and potassium carbonate (74 g, 540 mmol)and iodoethane (86 mL, 1.1 mol) were added thereto at room temperature,followed by stirring at room temperature overnight. The reactionsolution was partitioned with the addition of ethyl acetate and water,and extracted with ethyl acetate. The organic layer was washed withwater and brine and dried over sodium sulfate, followed by filtrationand concentration. The residue was purified by silica gel columnchromatography (developing solvent: ethyl acetate/hexane), therebyobtaining 2-ethoxy-6-fluorobenzaldehyde (59 g, 98%) as a white solid.

¹H-NMR (CDCl₃) δ: 10.47 (1H, s), 7.50-7.41 (1H, m), 6.77-6.67 (2H, m),4.16 (2H, q, J=6.8 Hz), 1.48 (3H, t, J=6.8 Hz). LCMS (ESI) m/z 169[M+H]⁺

Step 2: Synthesis of 1-ethoxy-2-ethynyl-3-fluorobenzene

The title compound was obtained as in step 1 of Example 51, except that2-ethoxy-6-fluorobenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.28-7.20 (1H, m), 6.74-6.63 (2H, m), 4.13 (2H, q,J=7.1 Hz), 3.50 (1H, s), 1.47 (3H, t, J=7.1 Hz).

Step 3: Synthesis of Example Compound 55

The title compound was obtained as in step 4 of Example 1, except that1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.58 (1H, s), 7.34-7.28 (1H, m), 6.88(1H, d, J=8.0 Hz), 6.82-6.74 (1H, m), 5.86 (1H, d, J=7.0 Hz), 4.85-4.81(1H, m), 4.33-4.29 (1H, m), 4.27-4.21 (3H, m), 3.40-3.34 (2H, m), 1.47(3H, t, J=7.0 Hz). LCMS (ESI) m/z 507 [M+H]⁺.

Step 4: Synthesis of4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidinehydrochloride

The title compound hydrochloride was obtained as in step 5 of Example 1.

¹H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.13 (1H, s), 7.44-7.38 (1H, m),7.01-6.91 (3H, m), 6.80-6.40 (1H, brs), 6.01 (1H, d, J=6.8 Hz),4.51-4.48 (1H, m), 4.24 (2H, q, J=7.0 Hz), 4.11-4.09 (1H, m), 4.06-4.02(1H, m), 3.24-3.19 (1H, m), 3.14-3.09 (1H, m), 1.38 (3H, t, J=7.0 Hz).LCMS (ESI) m/z 507 [M+H]⁺

Example 564-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-isopropoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-fluoro-6-isopropoxybenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that2-iodopropane was used in place of iodoethane.

¹H-NMR (CDCl₃) δ: 10.44 (1H, s), 7.44 (1H, dt, J=6.3, 8.5 Hz), 6.77 (1H,d, J=8.5 Hz), 6.68 (1H, dd, J=10.2, 8.5 Hz), 4.72-4.62 (1H, m), 1.41(6H, d, J=6.1 Hz).

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-isopropoxybenzene

The title compound was obtained as in step 1 of Example 51, except that2-fluoro-6-isopropoxybenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.22 (1H, dt, J=6.6, 8.4 Hz), 6.71-6.65 (2H, m),4.64-4.56 (1H, m), 3.47 (1H, s), 1.39 (6H, d, J=6.2 Hz).

Step 3: Synthesis of Example Compound 56

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-1-fluoro-3-isopropoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.57 (1H, s), 7.32-7.26 (1H, m), 6.89(1H, d, J=9.0 Hz), 6.78-6.73 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.85-4.81(1H, m), 4.79-4.71 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m),3.42-3.33 (2H, m), 1.41 (6H, d, J=5.9 Hz). LCMS (ESI) m/z 521 [M+H]⁺.

Example 574-Amino-5-[2-(4-cyano-2,6-difluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3,5-difluorobenzonitrile

The title compound was obtained as in step 1 of Example 51, except that3,5-difluoro-4-formylbenzonitrile was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.25 (2H, d, J=8.0 Hz), 3.73 (1H, s).

Step 2: Synthesis of Example Compound 57

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3,5-difluorobenzonitrile was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.26 (1H, s), 7.78 (1H, s), 7.58 (2H, d, J=7.1 Hz),5.88 (1H, d, J=6.8 Hz), 4.85-4.78 (1H, m), 4.33-4.30 (1H, m), 4.27-4.24(1H, m), 3.42-3.33 (2H, m). LCMS (ESI) m/z 506 [M+H]⁺.

Example 58 Methyl4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-benzoateStep 1: Synthesis of methyl 4-ethynyl-3,5-difluorobenzimidate

3,5-Difluoro-4-formylbenzonitrile (200 mg, 1.2 mmol) was dissolved inmethanol (3 mL). Then, potassium carbonate (331 mg, 24 mmol) was addedthereto at room temperature, anddimethyl(1-diazo-2-oxopropyl)phosphonate (0.22 mL, 1.4 mmol) was addedthereto under ice-cooling, followed by stirring under ice-cooling for 30minutes and at room temperature for additional 2 hours and 30 minutes.The reaction solution was partitioned with the addition of ethylacetate, a saturated aqueous sodium hydrogen carbonate solution, andwater, and the organic layer was washed with saturated saline. Afterbeing dried over sodium sulfate, the resulting product was filtered andconcentrated, and the residue was purified by silica gel columnchromatography (developing solvent: ethyl acetate/hexane), therebyobtaining methyl 4-ethynyl-3,5-difluorobenzimidate (172 mg).

LCMS (ESI) m/z 196 [M+H]⁺

Step 2: Synthesis of Example Compound 58

The title compound was obtained as in step 4 of Example 1, except thatmethyl 4-ethynyl-3,5-difluorobenzimidate was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.27 (1H, s), 7.76 (1H, s), 7.69 (2H, d, J=7.8 Hz),5.88 (1H, d, J=6.6 Hz), 4.85-4.78 (1H, m), 4.33-4.31 (1H, m), 4.27-4.24(1H, m), 3.94 (3H, s), 3.42-3.33 (2H, m). LCMS (ESI) m/z 539 [M+H]⁺.

Example 594-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of (2-ethynyl-3-fluorophenyl)(methyl)sulfane

The title compound was obtained as in step 1 of Example 51, except that2-fluoro-6-(methylthio)benzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.32-7.25 (1H, m), 6.94 (1H, d, J=8.1 Hz), 6.89-6.64(1H, m), 3.70 (1H, s), 2.51 (3H, s).

Step 2: Synthesis of Example Compound 59

The title compound was obtained as in step 4 of Example 1, except that(2-ethynyl-3-fluorophenyl)(methyl)sulfane was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.65 (1H, s), 7.37-7.31 (1H, m), 7.11(1H, d, J=8.0 Hz), 6.99-6.94 (1H, m), 5.88 (1H, d, J=6.8 Hz), 4.85-4.78(1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 3.42-3.33 (2H, m), 2.56(3H, s). LCMS (ESI) m/z 509 [M+H]⁺.

Example 604-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-fluoro-6-propoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-fluoro-6-propoxybenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that1-iodopropane was used in place of iodoethane.

¹H-NMR (CDCl₃) δ: 10.48 (1H, s), 7.46 (1H, dt, J=6.3, 8.5 Hz), 6.76 (1H,d, J=8.5 Hz), 6.71 (1H, dd, J=10.4, 8.5 Hz), 4.04 (2H, t, J=6.3 Hz),1.93-1.83 (2H, m), 1.56 (1H, s), 1.07 (3H, t, J=7.3 Hz). LCMS (ESI) m/z183 [M+H]⁺

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-propoxybenzene

The title compound was obtained as in step 1 of Example 51, except that2-fluoro-6-propoxybenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.27-7.20 (1H, m), 6.72-6.63 (2H, m), 4.01 (2H, t,J=6.5 Hz), 3.49 (1H, s), 1.81-1.91 (2H, m), 1.07 (3H, t, J=8.0 Hz).

Step 3: Synthesis of Example Compound 60

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-1-fluoro-3-propoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.57 (1H, s), 7.34-7.28 (1H, m), 6.88(1H, d, J=8.0 Hz), 6.80-6.74 (1H, m), 5.86 (1H, d, J=6.8 Hz), 4.85-4.78(1H, m), 4.33-4.31 (1H, m), 4.27-4.24 (1H, m), 4.13 (2H, t, J=6.7 Hz),3.42-3.33 (2H, m), 1.92-1.82 (2H, m), 1.07 (3H, t, 7.4 Hz). LCMS (ESI)m/z 521 [M+H]⁺.

Example 614-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-fluoro-6-(2,2,2-trifluoroethoxy)benzaldehyde

The title compound was obtained as in step 1 of Example 55, except that1,1,1-trifluoro-2-iodoethane was used in place of iodoethane.

¹H-NMR (CDCl₃) δ: 10.45 (1H, s), 7.53 (1H, dt, J=6.1, 8.6 Hz), 6.89 (1H,dd, J=9.8, 8.6 Hz), 6.77 (1H, d, J=8.6 Hz), 4.48 (2H, q, J=8.0 Hz). LCMS(ESI) m/z 223 [M+H]⁺

Step 2: Synthesis of 2-ethynyl-1-fluoro-3-(2,2,2-trifluoroethoxy)benzene

The title compound was obtained as in step 1 of Example 51, except that2-fluoro-6-(2,2,2-trifluoroethoxy)benzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.32-7.24 (1H, m), 6.88-6.81 (1H, m), 6.72 (1H, d,J=8.0 Hz), 4.45 (2H, q, J=8.0 Hz), 3.53 (1H, s).

Step 3: Synthesis of Example Compound 61

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-1-fluoro-3-(2,2,2-trifluoroethoxy)benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.60 (1H, s), 7.39-7.33 (1H, m), 6.98(1H, d, J=8.5 Hz), 6.93-6.89 (1H, m), 5.86 (1H, d, J=7.1 Hz), 4.84-4.82(1H, m), 4.76 (2H, q, J=8.4 Hz), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m),3.40-3.37 (2H, m). LCMS (ESI) m/z 561 [M+H]⁺.

Example 624-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethoxy-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-ethoxy-6-methoxybenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that2-hydroxy-6-methoxybenzaldehyde was used in place of2-fluoro-6-hydroxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 10.53 (1H, s), 7.42 (1H, t, J=8.5 Hz), 6.56 (2H, d,J=8.5 Hz), 4.15-4.08 (2H, q, J=7.0 Hz), 3.90 (3H, s), 1.46 (3H, t, J=7.0Hz). LCMS (ESI) m/z 181 [M+H]⁺

Step 2: Synthesis of 1-ethoxy-2-ethynyl-3-methoxybenzene

The title compound was obtained as in step 1 of Example 51, except that2-ethoxy-6-methoxybenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.23 (1H, t, J=8.4 Hz), 6.55-6.50 (2H, m), 4.12 (2H,q, J=7.0 Hz), 3.90 (3H, s), 3.53 (1H, s), 1.46 (3H, t, J=7.0 Hz). LCMS(ESI) m/z 177 [M+H]⁺

Step 3: Synthesis of Example Compound 62

The title compound was obtained as in step 4 of Example 1, except that1-ethoxy-2-ethynyl-3-methoxybenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.48 (1H, s), 7.27-7.23 (1H, m),6.67-6.64 (2H, m), 5.85 (1H, d, J=6.5 Hz), 4.88-4.80 (1H, m), 4.32-4.30(1H, m), 4.26-4.23 (1H, m), 4.18 (2H, q, J=7.0 Hz), 3.91 (3H, s),3.42-3.31 (2H, m), 1.45 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 519 [M+H]⁺.

Example 638-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2.3-d]pyrimidin-5-yl]ethynyl]-7-methoxyquinolineStep 1: Synthesis of 8-ethynyl-7-methoxyquinoline

The title compound was obtained as in step 1 of Example 51, except that7-methoxyquinoline-8-carbaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 9.03 (1H, dd, J=4.2, 1.8 Hz), 8.12 (1H, dd, J=8.3, 1.8Hz), 7.83 (1H, d, J=9.2 Hz), 7.35 (1H, d, J=9.2 Hz), 7.33 (1H, dd,J=8.3, 4.2 Hz), 4.10 (3H, s), 3.87 (1H, s). LCMS (ESI) m/z 184 [M+H]⁺

Step 2: Synthesis of Example Compound 63

The title compound was obtained as in step 4 of Example 1, except that8-ethynyl-7-methoxyquinoline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.92 (1H, dd, J=4.3, 1.7 Hz), 8.29 (1H, dd, J=8.3, 1.7Hz), 8.22 (1H, s), 7.92 (1H, d, J=9.0 Hz), 7.59 (1H, s), 7.54 (1H, d,J=9.0 Hz), 7.43 (1H, dd, J=8.3, 4.3 Hz), 5.89 (1H, d, J=6.8 Hz),4.61-4.59 (1H, m), 4.33 (1H, dd, J=5.4, 2.7 Hz), 4.29-4.26 (1H, m), 4.11(3H, s), 3.44-3.34 (2H, m). LCMS (ESI) m/z 526 [M+H]⁺.

Example 648-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazineStep 1: Synthesis of 7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

7-Fluoro-2,3-dihydro-1,4-benzoxazine (1.50 g, 9.79 mmol) was dissolvedin N,N-dimethylformamide (15 mL), and potassium carbonate (2.98 g, 21.5mmol) and methyl iodide (1.67 g, 11.8 mmol) were added thereto at roomtemperature. After the resulting mixture was stirred at room temperaturefor 3 days, water (60 mL) and ethyl acetate (60 mL) were sequentiallyadded thereto to partition the mixture into an aqueous layer and anorganic layer, followed by separation of each layer. The aqueous layerwas extracted with ethyl acetate (60 mL), and the obtained organiclayers were combined. The combined organic layer was sequentially washedwith water (60 mL) and saturated saline (60 mL), and dried overanhydrous sodium sulfate, followed by distilling off the solvent. Theresidue was purified by silica gel column chromatography (developingsolvent: ethyl acetate/hexane), thereby obtaining7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (1.09 g) as a light-yellowoil.

¹H-NMR (CDCl₃) δ: 6.58-6.51 (3H, m), 4.31 (2H, t, J=4.4 Hz), 3.20 (2H,t, J=4.4 Hz), 2.84 (3H, s). LCMS (ESI) m/z 168.1 [M+H]⁺

Step 2: Synthesis of7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde

7-Fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (1.07 g, 6.40 mmol) wasdissolved in tetrahydrofuran (17.1 mL), and n-butyllithium (a 1.6 Mhexane solution, 4.83 mL) was added thereto dropwise with stirring at−78° C. After the mixture was stirred at −78° C. for 3 hours,N,N-dimethylformamide (702 mg, 9.60 mmol) was added thereto dropwise,and the temperature was increased to 0° C. A saturated aqueous ammoniumchloride solution (40 mL) and ethyl acetate (40 mL) were sequentiallyadded thereto, followed by separation of each layer. The aqueous layerwas extracted twice with ethyl acetate (40 mL), and the obtained organiclayers were combined. The combined organic layer was sequentially washedwith a saturated aqueous ammonium chloride solution (100 mL), water (100mL), and saturated saline (100 mL), and dried over anhydrous sodiumsulfate, followed by distilling off the solvent. The residue waspurified by silica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde (1.13 g) asa bright yellow solid.

¹H-NMR (CDCl₃) δ: 10.38 (1H, d, J=2.2 Hz), 6.78-6.73 (1H, m), 6.62-6.57(1H, m), 4.45-4.42 (2H, m), 3.28-3.25 (2H, m), 2.87 (3H, d, J=1.8 Hz).LCMS (ESI) m/z 196.2 [M+H]⁺

Step 3: Synthesis of8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

The title compound was obtained as in step 1 of Example 51, except that7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine-8-carbaldehyde was used inplace of 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 6.59-6.56 (2H, m), 4.43 (2H, t, J=4.4 Hz), 3.49 (1H,s), 3.22 (2H, t, J=4.4 Hz), 2.84 (3H, s). LCMS (ESI) m/z 192.4 [M+H]⁺

Step 4: Synthesis of Example Compound 64

The title compound was obtained as in step 4 of Example 1, except that8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine was used inplace of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.88 (1H, s), 7.38 (1H, dd, J=7.3, 4.8Hz), 6.78-6.69 (2H, m), 6.60 (2H, s), 5.91 (1H, d, J=7.3 Hz), 5.40 (1H,s), 5.24 (1H, s), 4.58 (1H, t, J=6.2 Hz), 4.43 (2H, t, J=4.2 Hz),4.12-4.07 (1H, m), 4.07-4.02 (1H, m), 3.26 (2H, t, J=4.2 Hz), 3.23-3.16(1H, m), 3.15-3.07 (1H, m), 2.82 (3H, s). LCMS (ESI) m/z 534.3 [M+H]⁺.

Step 5: Synthesis of8-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazinehydrochloride

The title compound hydrochloride was obtained as in step 5 of Example 1.

¹H-NMR (DMSO-D₆) δ: 8.47 (1H, s), 8.23 (1H, s), 6.82-6.76 (2H, m), 6.06(1H, d, J=6.8 Hz), 4.49-4.45 (3H, m), 4.12 (1H, dd, J=5.2, 2.8 Hz), 4.05(1H, dt, J=5.6, 2.8 Hz), 3.28 (2H, t, J=4.4 Hz), 3.23 (1H, dd, J=14.0,6.0 Hz), 3.13 (1H, dd, J=14.0, 6.0 Hz), 2.84 (3H, s). LCMS (ESI) m/z534.3 [M+H]⁺

Example 654-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2,4-dimethoxy-3-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 3-ethynyl-2,4-dimethoxypyridine

The title compound was obtained as in step 1 of Example 51, except that2,4-dimethoxynicotinaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 8.05 (1H, d, J=6.1 Hz), 6.54 (1H, d, J=6.1 Hz), 4.02(3H, s), 3.95 (3H, s), 3.58 (1H, s). LCMS (ESI) m/z 164 [M+H]⁺

Step 2: Synthesis of Example Compound 65

The title compound was obtained as in step 4 of Example 1, except that3-ethynyl-2,4-dimethoxypyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 8.08 (1H, d, J=6.1 Hz), 7.85 (1H, d,J=2.0 Hz), 7.35 (1H, s), 6.89 (1H, d, J=6.1 Hz), 6.59 (2H, s), 5.91 (1H,d, J=7.1 Hz), 4.58 (1H, t, J=5.7 Hz), 4.11-4.08 (1H, m), 4.06-4.03 (1H,m), 3.95 (6H, d, J=2.7 Hz), 3.35 (2H, s), 3.22-3.10 (2H, m). LCMS (ESI)m/z 506 [M+H]⁺.

Example 664-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-(ethylthio)-6-fluorobenzaldehyde

Ethyl (3-fluorophenyl)sulfane (2.0 g, 12.8 mmol) was dissolved intetrahydrofuran (30 mL), and n-butyllithium (a 2.69 M hexane solution,5.71 mL) was added thereto dropwise while being stirred with cooling at−78° C. After the resulting mixture was stirred at −78° C. for 30minute, N,N-dimethylformamide (2.95 mL, 38.4 mmol) was added thereto,followed by stirring for 1 hour. A saturated aqueous ammonium chloridesolution was added to the reaction liquid, followed by extraction withethyl acetate. After the solvent was distilled off, the residue waspurified by column chromatography (developing solvent: hexane/ethylacetate), thereby obtaining 2-(ethylthio)-6-fluorobenzaldehyde (430 mg,18%) as a light-yellow solid.

¹H-NMR (CDCl₃) δ: 10.52 (1H, s), 7.51-7.46 (1H, m), 7.13 (1H, d, J=8.8Hz), 6.91 (1H, t, J=8.8 Hz), 2.99 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3Hz).

Step 2: Synthesis of ethyl(2-ethynyl-3-fluorophenyl)sulfane

The title compound was obtained as in step 1 of Example 51, except that2-(ethylthio)-6-fluorobenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.30-7.24 (1H, m), 7.03 (1H, d, J=8.1 Hz), 6.89 (1H,dd, J=8.8, 8.1 Hz), 3.71 (1H, s), 3.03 (2H, q, J=7.3 Hz), 1.40 (3H, t,J=7.3 Hz).

Step 3: Synthesis of Example Compound 66

The title compound was obtained as in step 4 of Example 1, except thatethyl (2-ethynyl-3-fluorophenyl)sulfane was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, s), 7.95 (1H, s), 7.91 (1H, d, J=7.0 Hz),7.46 (1H, t, J=7.7 Hz), 7.41-7.32 (2H, m), 7.22 (1H, d, J=8.1 Hz), 7.12(1H, t, J=8.8 Hz), 6.57 (2H, s), 5.91 (1H, d, J=7.0 Hz), 5.37 (1H, brs),5.21 (1H, brs), 4.57 (1H, brs), 4.09-4.06 (1H, brm), 4.04-4.01 (1H,brm), 3.23-3.05 (2H, m), 1.28 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 523[M+H]⁺.

Example 674-Amino-5-[2-[2,6-difluoro-4-(triazol-2-ylmethoxy)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of4-((2H-1,2,3-triazol-2-yl)methoxy)-2,6-difluorobenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that2,6-difluoro-4-hydroxybenzaldehyde was used in place of2-fluoro-6-hydroxybenzaldehyde, and that 2-(chloromethyl)triazole wasused in place of iodoethane.

¹H-NMR (CDCl₃) δ: 10.21 (1H, s), 7.76 (2H, s), 6.88 (2H, d, J=10.0 Hz),6.30 (2H, s). LCMS (ESI) m/z 240 [M+H]⁺

Step 2: Synthesis of2-((4-ethynyl-3,5-difluorophenoxy)methyl)-2H-1,2,3-triazole

The title compound was obtained as in step 1 of Example 51, except that4-((2H-1,2,3-triazol-2-yl)methoxy)-2,6-difluorobenzaldehyde was used inplace of 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.74 (2H, s), 7.26 (2H, s), 6.82 (1H, d, J=8.5 Hz),6.24 (1H, s), 3.43 (1H, s). LCMS (ESI) m/z 236 [M+H]⁺

Step 3: Synthesis of Example Compound 67

The title compound was obtained as in step 4 of Example 1, except that2-((4-ethynyl-3,5-difluorophenoxy)methyl)-2H-1,2,3-triazole was used inplace of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.99 (2H, s), 7.96 (1H, s), 7.36-7.31(1H, brs), 7.19 (2H, d, J=9.5 Hz), 6.61-6.57 (2H, s), 6.52 (2H, s), 5.91(1H, d, J=7.1 Hz), 5.40 (1H, d, J=6.6 Hz), 5.23 (1H, d, J=4.1 Hz),4.59-4.54 (1H, m), 4.10-4.06 (1H, m), 4.05-4.02 (1H, m), 3.22-3.16 (1H,m), 3.10-3.06 (1H, m). LCMS (ESI) m/z 578 [M+H]⁺.

Example 684-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-(ethylamino)-6-fluoro-phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2-(ethylamino)-6-fluorobenzaldehyde

The title compound was obtained as in step 1 of Example 23, except that2,6-difluorobenzaldehyde and ethylamine were used in place of2-ethynyl-1,3,5-trifluorobenzene and morpholine.

¹H-NMR (CDCl₃) δ: 10.28 (1H, s), 8.66 (1H, brs), 7.35-7.29 (1H, m), 6.45(1H, d, J=8.1 Hz), 6.27 (1H, dd, J=11.4, 8.1 Hz), 3.32-3.25 (2H, m),1.33 (3H, t, J=7.3 Hz). LRMS (ESI) m/z 168 [M+H]⁺

Step 2: Synthesis of N-ethyl-2-ethynyl-3-fluoroaniline

The title compound was obtained as in step 1 of Example 51, except that2-(ethylamino)-6-fluorobenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.13 (1H, dd, J=14.7, 7.7 Hz), 6.38-6.34 (2H, m),4.62-4.56 (1H, brm), 3.62 (1H, s), 3.21 (2H, dq, J=7.3, 6.6 Hz), 1.29(3H, t, J=7.3 Hz). LRMS (ESI) m/z 164 [M+H]⁺

Step 3: Synthesis of Example Compound 68

The title compound was obtained as in step 4 of Example 1, except thatN-ethyl-2-ethynyl-3-fluoroaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.55 (1H, s), 7.26 (1H, ddd, J=8.4, 8.4,7.0 Hz), 6.82 (1H, d, J=8.4 Hz), 6.74 (1H, t, J=8.4 Hz), 5.87 (1H, d,J=6.6 Hz), 4.79 (1H, t, J=6.6 Hz), 4.30 (1H, dd, J=5.5, 2.6 Hz),4.23-4.17 (2H, m), 4.19 (1H, q, J=7.0 Hz), 3.56-3.54 (2H, m), 1.46 (3H,t, J=7.0 Hz). LCMS (ESI) m/z 506 [M+H]⁺.

Example 69 4-Amino-5-[2-(2,4-difluoro-3-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 3-ethynyl-2,4-difluoropyridine

The title compound was obtained as in step 1 of Example 51, except that2,4-difluoronicotinaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (ACETONE-D₆) δ: 8.38 (1H, dd, J=8.2, 5.7 Hz), 7.44-7.40 (1H, m),4.46 (1H, s). LCMS (ESI) m/z 140 [M+H]⁺

Step 2: Synthesis of Example Compound 69

The title compound was obtained as in step 4 of Example 1, except that3-ethynyl-2,4-difluoropyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 8.18 (1H, dd, J=8.2, 5.8 Hz), 7.73 (1H,s), 7.27 (1H, dd, J=8.2, 5.8 Hz), 5.87 (1H, d, J=6.6 Hz), 4.82 (1H, d,J=5.9 Hz), 4.32 (1H, dd, J=5.5, 2.6 Hz), 4.26 (1H, q, J=3.1 Hz),3.43-3.33 (2H, m). LCMS (ESI) m/z 482 [M+H]⁺.

Example 704-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfonyl-6-fluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde

The title compound was obtained as in step 1 of Example 23, except that2,4,6-trifluorobenzaldehyde and pyrrolidine were used in place of2-ethynyl-1,3,5-trifluorobenzene and morpholine.

¹H-NMR (CDCl₃) δ: 10.04 (1H, s), 6.01 (2H, d, J=12.8 Hz), 3.35-3.32 (4H,m), 2.07-2.03 (4H, m). LCMS (ESI) m/z 212 [M+H]⁺

Step 2: Synthesis of2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde

2,6-Difluoro-4-(pyrrolidin-1-yl)benzaldehyde (3.7 g, 18 mmol) wasdissolved in N,N-dimethylformamide (37 mL), and sodium ethanethiolate(1.6 g, 18 mmol) was added thereto, followed by stirring at roomtemperature for 30 minutes. Ethyl acetate, water, and a saturatedaqueous sodium hydrogen carbonate solution were added to the reactionsolution, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated sodium chlorideaqueous solution, and dried over sodium sulfate, followed by distillingoff the solvent. The residue was purified by silica gel columnchromatography (developing solvent: chloroform), thereby obtaining2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (4.4 g) as awhite solid.

¹H-NMR (CDCl₃) δ: 10.18 (1H, s), 6.10 (1H, d, J=2.0 Hz), 5.98 (1H, dd,J=14.3, 2.0 Hz), 3.39-3.35 (4H, m), 2.91 (2H, q, J=7.3 Hz), 2.07-2.04(4H, m), 1.41 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 254 [M+H]⁺

Step 3: Synthesis of2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde

2-(Ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (79 mg, 0.31mmol) was dissolved in dichloromethane (1.6 mL), and 3-chloroperbenzoicacid (110 mg, 0.65 mmol) was added thereto in an ice bath, followed bystirring for 2 hours in an ice bath. 3-chloroperbenzoic acid (56 mg,0.32 mmol) was added to the resulting mixture in an ice bath, followedby stirring for 1 hour in an ice bath. Thereafter, 3-chloroperbenzoicacid (10 mg, 0.058 mmol) was further added thereto in an ice bath,followed by stirring for 30 minutes in an ice bath. Chloroform, water,and a saturated aqueous sodium hydrogen carbonate solution were added inan ice bath to the reaction solution, and the aqueous solution wasextracted with chloroform. The organic layer was washed with a saturatedsodium chloride aqueous solution, and dried over sodium sulfate,followed by distilling off the solvent. The residue was purified bysilica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde (54 mg, 0.19mmol, 62%) as a yellow solid.

¹H-NMR (CDCl₃) δ: 10.28 (1H, s), 7.19 (1H, d, J=2.6 Hz), 6.33 (1H, dd,J=13.9, 2.6 Hz), 3.62 (2H, q, J=7.5 Hz), 3.50-3.40 (4H, m), 2.11-2.08(4H, m), 1.31 (3H, t, J=7.5 Hz). LCMS (ESI) m/z 286 [M+H]⁺

Step 4: Synthesis of1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine

The title compound was obtained as in step 1 of Example 51, except that2-(ethylsulfonyl)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde was used inplace of 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.01 (1H, d, J=2.3 Hz), 6.38 (1H, dd, J=11.9, 2.3 Hz),3.63 (1H, s), 3.49 (2H, q, J=7.4 Hz), 3.36-3.32 (4H, m), 2.07-2.04 (4H,m), 1.27 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 282 [M+H]⁺

Step 5: Synthesis of Example Compound 70

The title compound was obtained as in step 4 of Example 1, except that1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine was used inplace of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.61 (1H, s), 7.01 (1H, d, J=2.3 Hz),6.66 (1H, dd, J=12.4, 2.3 Hz), 5.86 (1H, d, J=7.1 Hz), 4.85-4.81 (1H,m), 4.32-4.30 (1H, m), 4.27-4.24 (1H, m), 3.49 (2H, q, J=7.3 Hz),3.40-3.36 (4H, m), 3.31-3.30 (2H, m), 2.10-2.07 (4H, m), 1.25 (3H, t,J=7.3 Hz). LCMS (ESI) m/z 624 [M+H]⁺.

Example 714-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-5-methoxy-4-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3-fluoro-5-methoxypyridine

The title compound was obtained as in step 1 of Example 51, except that3-fluoro-5-methoxyisonicotinaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 8.21-8.17 (2H, m), 4.03 (3H, s), 3.69 (1H, s). LCMS(ESI) m/z 152 [M+H]⁺

Step 2: Synthesis of Example Compound 71

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3-fluoro-5-methoxypyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, d, J=7.8 Hz), 8.37 (1H, s), 8.20 (1H, s),8.05 (1H, s), 7.32-7.29 (1H, brs), 6.58 (2H, s), 5.93 (1H, d, J=6.8 Hz),5.41-5.38 (1H, brs), 5.23-5.21 (1H, brs), 4.59-4.57 (1H, m), 4.08-4.04(2H, m), 4.07 (3H, s), 3.22-3.18 (1H, m), 3.12-3.08 (1H, m). LCMS (ESI)m/z 494 [M+H]⁺.

Example 724-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 1 of Example 23, except that2,4,6-trifluorobenzaldehyde and (R)-pyrrolidin-3-ol were used in placeof 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

¹H-NMR (CDCl₃) δ: 10.05 (1H, s), 6.03 (2H, d, J=12.4 Hz), 4.70-4.66 (1H,m), 3.60-3.53 (2H, m), 3.48-3.42 (1H, m), 3.36-3.31 (1H, m), 2.21-2.12(2H, m), 1.79 (1H, d, J=3.9 Hz). LCMS (ESI) m/z 228 [M+H]⁺

Step 2: Synthesis of2-ethylsulfanyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 2 of Example 70, except that2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde was used inplace of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 10.19 (1H, s), 6.11 (1H, d, J=2.2 Hz), 6.00 (1H, dd,J=14.1, 2.2 Hz), 4.69-4.66 (1H, m), 3.63-3.57 (2H, m), 3.50-3.45 (1H,m), 3.41-3.35 (1H, m), 2.91 (2H, q, J=7.4 Hz), 2.21-2.14 (2H, m), 1.77(1H, d, J=4.1 Hz), 1.41 (3H, t, J=7.4 Hz). LCMS (ESI) m/z 270 [M+H]⁺

Step 3: Synthesis of2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 3 of Example 70, except that2-ethylsulfanyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehydewas used in place of2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 10.30 (1H, s), 7.20 (1H, d, J=2.4 Hz), 6.36 (1H, dd,J=14.0, 2.4 Hz), 4.73-4.71 (1H, m), 3.67-3.42 (4H, m), 3.46-3.42 (1H,m), 3.35-3.32 (1H, m), 2.21-2.17 (2H, m), 1.76 (1H, d, J=3.4 Hz), 1.32(3H, t, J=7.6 Hz). LCMS (ESI) m/z 302 [M+H]⁺

Step 4: Synthesis of (3R)-1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidin-3-ol

The title compound was obtained as in step 1 of Example 51, except that2-ethylsulfonyl-6-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]benzaldehydewas used in place of 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.03 (1H, d, J=2.4 Hz), 6.41 (1H, dd, J=11.7, 2.4 Hz),4.69-4.67 (1H, m), 3.65 (1H, s), 3.61-3.43 (5H, m), 3.35 (1H, d, J=11.0Hz), 2.23-2.12 (2H, m), 1.69 (1H, d, J=3.7 Hz), 1.27 (3H, t, J=7.4 Hz).LCMS (ESI) m/z 298 [M+H]⁺

Step 5: Synthesis of Example Compound 72

The title compound was obtained as in step 4 of Example 1, except that(3R)-1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidin-3-ol wasused in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.62 (1H, s), 7.01 (1H, d, J=2.3 Hz),6.67 (1H, dd, J=12.2, 2.3 Hz), 5.87 (1H, d, J=7.1 Hz), 4.85-4.79 (1H,m), 4.58-4.54 (1H, m), 4.32-4.30 (1H, m), 4.26-4.24 (1H, m), 3.58-3.43(6H, m), 3.42-3.33 (2H, m), 2.22-2.14 (1H, m), 2.12-2.05 (1H, m), 1.25(3H, t, J=7.4 Hz). LCMS (ESI) m/z 640 [M+H]⁺.

Example 734-Amino-5-[2-(2-chloro-6-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-chloro-2-ethynyl-3-fluorobenzene

The title compound was obtained as in step 1 of Example 51, except that2-chloro-6-fluorobenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.29-7.21 (2H, m), 7.05-7.00 (1H, m), 3.61 (1H, s).

Step 2: Synthesis of Example Compound 73

The title compound was obtained as in step 4 of Example 1, except that1-chloro-2-ethynyl-3-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.67 (1H, s), 7.37-7.30 (2H, m),7.18-7.13 (1H, m), 5.87 (1H, d, J=7.1 Hz), 4.85-4.82 (1H, m), 4.33-4.31(1H, m), 4.27-4.25 (1H, m), 3.43-3.34 (2H, m). LCMS (ESI) m/z 497[M+H]⁺.

Example 744-[4-[2-[4-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]-1,1-dioxo-1,4-thiazinaneStep 1: Synthesis of4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine-1,1-dioxide

The title compound was obtained as in step 3 of Example 70, except that4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine was used in place of2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 6.40 (2H, d, J=10.2 Hz), 3.92-3.88 (4H, m), 3.42 (1H,s), 3.11-3.06 (4H, m). LCMS (ESI) m/z 272 [M+H]⁺

Step 2: Synthesis of Example Compound 74

The title compound was obtained as in step 4 of Example 1, except that4-(4-ethynyl-3,5-difluorophenyl)thiomorpholine-1,1-dioxide was used inplace of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.90 (1H, s), 7.36-7.32 (1H, m), 6.95(2H, d, J=11.4 Hz), 6.60 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.39 (1H, d,J=6.2 Hz), 5.24-5.22 (1H, m), 4.60-4.55 (1H, m), 4.12-4.08 (1H, m),4.06-4.03 (1H, m), 3.95-3.89 (4H, m), 3.25-3.17 (1H, m), 3.17-3.09 (5H,m). LCMS (ESI) m/z 614 [M+H]⁺.

Example 754-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[2-ethylsulfonyl-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of2,6-difluoro-4-[(3R)-fluoropyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 1 of Example 23, except that2,4,6-trifluorobenzaldehyde and (R)-3-fluoropyrrolidine were used inplace of 2-ethynyl-1,3,5-trifluorobenzene and morpholine.

¹H-NMR (CDCl₃) δ: 10.07 (1H, s), 6.04 (2H, d, J=12.5 Hz), 5.47-5.32 (1H,m), 3.64-3.51 (4H, m), 2.50-2.41 (1H, m), 2.28-2.08 (1H, m). LCMS (ESI)m/z 230 [M+H]⁺

Step 2: Synthesis of2-(ethylthio)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 2 of Example 70, except that2,6-difluoro-4-[(3R)-fluoropyrrolidin-1-yl]benzaldehyde was used inplace of 2,6-difluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 10.21 (1H, s), 6.11 (1H, d, J=1.8 Hz), 6.01 (1H, dd,J=13.9, 1.8 Hz), 5.47-5.33 (1H, m), 3.70-3.52 (4H, m), 2.92 (2H, q,J=7.3 Hz), 2.49-2.40 (1H, m), 2.28-2.09 (1H, m), 1.41 (3H, t, J=7.3 Hz).LCMS (ESI) m/z 272 [M+H]⁺

Step 3: Synthesis of2-(ethylsulfonyl)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde

The title compound was obtained as in step 3 of Example 70, except that2-(ethylthio)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehyde wasused in place of 2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 10.31 (1H, s), 7.21 (1H, d, J=2.3 Hz), 6.38 (1H, dd,J=13.7, 2.3 Hz), 5.51-5.35 (1H, m), 3.74-3.60 (6H, m), 2.53-2.45 (1H,m), 2.29-2.14 (1H, m), 1.32 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 304 [M+H]⁺

Step 4: Synthesis of(3R)-1-(3-ethylsulfonyl-4-ethynyl-5-fluoro-phenyl)-3-fluoro-pyrrolidine

The title compound was obtained as in step 1 of Example 51, except that2-(ethylsulfonyl)-6-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]benzaldehydewas used in place of 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.03 (1H, d, J=2.4 Hz), 6.42 (1H, dd, J=11.7, 2.4 Hz),5.47-5.33 (1H, m), 3.66-3.64 (2H, m), 3.61-3.46 (5H, m), 2.49-2.40 (1H,m), 2.29-2.11 (1H, m), 1.27 (3H, t, J=7.5 Hz). LCMS (ESI) m/z 300 [M+H]⁺

Step 5: Synthesis of Example Compound 75

The title compound was obtained as in step 4 of Example 1, except that(3R)-1-(3-ethylsulfonyl-4-ethynyl-5-fluoro-phenyl)-3-fluoro-pyrrolidinewas used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.20 (1H, s), 7.60 (1H, s), 6.99 (1H, d, J=2.6 Hz),6.66 (1H, dd, J=12, 2.6 Hz), 5.86 (1H, d, J=7.0 Hz), 5.47-5.34 (1H, m),4.81-4.78 (1H, m), 4.31-4.29 (1H, m), 4.25-4.23 (1H, m), 3.70-3.44 (6H,m), 3.41-3.32 (2H, m), 2.42-2.15 (2H, m), 1.24 (3H, t, J=7.3 Hz). LCMS(ESI) m/z 642 [M+H]⁺.

Example 764-Amino-5-[2-(5-benzyloxypyrimidin-2-yl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 5-(benzyloxy)-2-bromopyrimidine

2-Bromopyrimidin-5-ol (200 mg, 1.1 mmol) was dissolved in a liquidmixture of tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL).Then, potassium carbonate (170 mg, 1.3 mmol) and benzyl bromide (0.15mL, 1.3 mmol) were added thereto at room temperature, followed bystirring at room temperature for 6 hours. The reaction solution waspartitioned with ethyl acetate and water, and the organic layer waswashed with water and saturated saline. The resulting product was driedover sodium sulfate, followed by filtration and concentration, and theresidue was purified by silica gel column chromatography (developingsolvent: ethyl acetate/hexane), thereby obtaining5-(benzyloxy)-2-bromopyrimidine (200 mg, 0.75 mmol, 66%) as a whitepowder.

¹H-NMR (CDCl₃) δ: 8.31 (2H, s), 7.45-7.36 (5H, m), 5.15 (2H, s). LCMS(ESI) m/z 265 [M+H]⁺

Step 2: Synthesis of5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine

5-(Benzyloxy)-2-bromopyrimidine (200 mg, 0.75 mmol),ethynyltriisopropylsilane (0.34 mL, 1.5 mmol),bis(triphenylphosphine)palladium (II) dichloride (53 mg, 0.075 mmol),copper iodide (14 mg, 0.075 mmol), and diisopropylethylamine (0.26 mL,1.5 mmol) were suspended in tetrahydrofuran (2 mL). The reactionsolution was stirred at 70° C. for 1 hour and 30 minutes, and filteredthrough a celite bed, followed by distilling off the solvent. Theresidue was purified by silica gel column chromatography (developingsolvent: ethyl acetate/hexane), thereby obtaining5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine (120 mg, 0.32mmol, 43%) as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.42 (2H, s), 7.43-7.36 (5H, m), 5.18 (2H, s),1.17-1.13 (21H, m). LCMS (ESI) m/z 367 [M+H]⁺

Step 3: Synthesis of 5-(benzyloxy)-2-ethynylpyrimidine

5-(Benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine (120 mg, 0.32mmol) was dissolved in tetrahydrofuran (1 mL), and a tetrabutylammoniumfluoride solution (1 M tetrahydrofuran solution, 0.38 mL, 0.38 mmol) wasadded thereto at room temperature, followed by stirring at roomtemperature for 30 minutes.

After the solvent was distilled off, the residue was purified by silicagel column chromatography (developing solvent: ethyl acetate/hexane),thereby obtaining 5-(benzyloxy)-2-ethynylpyrimidine (45 mg, 0.21 mmol,67%) as a yellow powder.

¹H-NMR (CDCl₃) δ: 8.43 (2H, s), 7.44-7.38 (5H, m), 5.19 (2H, s), 3.04(1H, s). LCMS (ESI) m/z 211 [M+H]⁺

Step 4: Synthesis of Example Compound 76

The title compound was obtained as in step 4 of Example 1, except that5-(benzyloxy)-2-ethynylpyrimidine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.57 (2H, s), 8.26 (1H, s), 7.75 (1H, s), 7.49-7.33(5H, m), 5.87 (1H, d, J=6.8 Hz), 5.30 (2H, s), 4.84-4.79 (1H, m),4.32-4.27 (1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z553 [M+H]⁺.

Example 774-Amino-5-[2-(4-benzyloxy-2-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of ((4-(benzyloxy)-2-fluorophenyl)ethynyl)trimethylsilane

The title compound was obtained as in step 2 of Example 76, except that4-(benzyloxy)-2-fluoro-1-iodobenzene and ethynyltrimethylsilane wereused in place of 5-(benzyloxy)-2-bromopyrimidine andethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.43-7.33 (6H, m), 6.77 (1H, dd, J=10.4, 2.8 Hz),6.70-6.67 (1H, m), 5.04 (2H, s), 0.25 (9H, s).

Step 2: Synthesis of 4-(benzyloxy)-1-ethynyl-2-fluorobenzene

The title compound was obtained as in step 3 of Example 76, except that4((4-(benzyloxy)-2-fluorophenyl)ethynyl)trimethylsilane was used inplace of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.43-7.29 (6H, m), 6.66-6.79 (2H, m), 5.04 (2H, s),3.25 (1H, s).

Step 3: Synthesis of Example Compound 77

The title compound was obtained as in step 4 of Example 1, except that4-(benzyloxy)-1-ethynyl-2-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.56 (1H, s), 7.40-7.26 (6H, m),6.87-6.84 (2H, m), 5.85 (1H, d, J=6.8 Hz), 5.12 (2H, s), 4.83-4.81 (1H,m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI)m/z 569 [M+H]⁺.

Example 784-Amino-5-[2-[4-(benzylamino)phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of N-benzyl-4-((triisopropylsilyl)ethynyl)aniline

The title compound was obtained as in step 2 of Example 76, except thatN-benzyl-4-iodoaniline and ethynyltriisopropylsilane were used in placeof 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.37-7.25 (7H, m), 6.53 (2H, d, J=8.8 Hz), 4.34 (2H,s), 1.12-1.05 (21H, m). LCMS (ESI) m/z 364 [M+H]⁺

Step 2: Synthesis of N-benzyl-4-ethynylaniline

The title compound was obtained as in step 3 of Example 76, except thatN-benzyl-4-((triisopropylsilyl)ethynyl)aniline was used in place of5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.39-7.25 (7H, m), 6.55 (2H, d, J=8.0 Hz), 4.35 (2H,s), 4.28-4.19 (1H, brs), 2.96 (1H, s). LCMS (ESI) m/z 208 [M+H]⁺

Step 3: Synthesis of Example Compound 78

The title compound was obtained as in step 4 of Example 1, except thatN-benzyl-4-ethynylaniline was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 7.60 (1H, s), 7.36-7.20 (7H, m), 6.60(2H, d, J=8.8 Hz), 5.93 (1H, d, J=6.6 Hz), 4.73-4.70 (1H, m), 4.35 (2H,s), 4.31-4.29 (1H, m), 4.25-4.22 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI)m/z 550 [M+H]⁺.

Example 792-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-fluorobenzamideStep 1: Synthesis of 3-fluoro-2-((trimethylsilyl) ethynyl)benzamide

The title compound was obtained as in step 2 of Example 76, except that3-fluoro-2-iodobenzamide and ethynyltrimethylsilane were used in placeof 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.96 (1H, d, J=7.8 Hz), 7.83-7.55 (1H, brs), 7.45-7.40(1H, m), 7.28-7.22 (1H, m), 6.19-5.72 (1H, brs), 0.31 (9H, s). LCMS(ESI) m/z 236 [M+H]⁺

Step 2: Synthesis of 2-ethynyl-3-fluorobenzamide

The title compound was obtained as in step 3 of Example 76, except that3-fluoro-2-((trimethylsilyl)ethynyl)benzamide was used in place of5-(benzyloxy)-2-((triisopropylsilyl) ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.89-7.86 (1H, m), 7.46 (1H, dt, J=5.4, 8.0 Hz),7.30-7.21 (2H, m), 6.29-5.45 (1H, brs), 3.77 (1H, s). LCMS (ESI) m/z 164[M+H]⁺

Step 3: Synthesis of Example Compound 79

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-3-fluorobenzamide was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.66 (1H, s), 7.47-7.41 (2H, m),7.35-7.30 (1H, m), 5.87 (1H, d, J=6.8 Hz), 4.82-4.75 (1H, m), 4.32-4.29(1H, m), 4.26-4.24 (1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 506[M+H]⁺.

Example 804-Amino-5-[2-(3,5-difluoro-2-methoxy-4-pyridyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3,5-difluoro-2-methoxypyridine

2,3,5-Trifluoro-4-iodopyridine (500 mg, 1.93 mmol) was dissolved inmethanol (3 mL), and sodium methoxide (a 5 M methanol solution, 1.15 mL)was added thereto at room temperature, followed by stirring at roomtemperature overnight. The reaction solution was partitioned betweenethyl acetate and water, and the organic layer was separated andsequentially washed with water and brine. The solvent was distilled off,and the residue was purified by silica gel column chromatography(developing solvent: ethyl acetate/hexane), thereby obtaining the targetproduct (376 mg) as an oil mixture of4-ethynyl-3,5-difluoro-2-methoxypyridine and4-ethynyl-3-fluoro-2,5-dimethoxypyridine.

The synthesis was performed as in steps 2 and 3 of Example 76 by usingthe obtained mixture, followed by separation and purification by silicagel column chromatography (developing solvent: ethyl acetate/hexane) togive the title compound.

¹H-NMR (CDCl₃) δ: 7.87 (1H, s), 4.02 (3H, s), 3.73 (1H, s)

Step 2: Synthesis of Example Compound 80

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3,5-difluoro-2-methoxypyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, s), 8.19 (1H, s), 8.14 (1H, s), 7.32-7.29(1H, m), 6.59 (2H, s), 5.94 (1H, d, J=6.6 Hz), 5.41 (1H, d, J=6.6 Hz),5.24 (1H, d, J=4.4 Hz), 4.58 (1H, ddd, J=7.3, 6.2, 4.4 Hz), 4.11-4.04(2H, m), 3.96 (3H, s). LCMS (ESI) m/z 512 [M+H]⁺.

Example 814-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-2,5-dimethoxy-4-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-ethynyl-3-fluoro-2,5-dimethoxypyridine

In accordance with step 1 of Example 80, the title compound wasobtained.

¹H-NMR (CDCl₃) δ: 7.76 (1H, s), 4.01 (3H, s), 3.97 (3H, s), 3.66 (1H,s).

Step 2: Synthesis of Example Compound 81

The title compound was obtained as in step 4 of Example 1, except that4-ethynyl-3-fluoro-2,5-dimethoxypyridine was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.26 (1H, s), 7.83 (1H, s), 7.75 (1H, s), 5.89 (1H, d,J=6.6 Hz), 4.85-4.82 (3H, m), 4.34-4.32 (1H, m), 4.29-4.26 (1H, m), 4.04(3H, s), 3.99 (3H, s), 3.70-3.67 (1H, m), 3.58-3.56 (1H, m), 3.42 (1H,dd, J=12.5, 4.4 Hz), 3.37 (1H, dd, J=12.5, 3.7 Hz). LCMS (ESI) m/z 524[M+H]⁺.

Example 824-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfanylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-ethylsulfanyl-2-ethynyl-benzene

The title compound was obtained as in step 2 and step 3 of Example 76,except that 1-bromo-2-ethylsulfanyl-benzene was used in place of5-(benzyloxy)-2-bromopyrimidine.

¹H-NMR (CDCl₃) δ: 7.49 (1H, dd, J=7.5, 1.3 Hz), 7.33-7.25 (2H, m), 7.12(1H, dt, J=1.5, 7.3 Hz), 3.47 (1H, s), 3.01 (2H, q, J=7.5 Hz), 1.37 (3H,dd, J=9.5, 5.1 Hz).

Step 2: Synthesis of Example Compound 82

The title compound was obtained as in step 4 of Example 1, except that1-ethylsulfanyl-2-ethynyl-benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.91 (1H, s), 7.52 (1H, dd, J=7.7, 1.1Hz), 7.44-7.36 (3H, m), 7.23 (1H, dt, J=1.5, 7.3 Hz), 6.61 (2H, s), 5.93(1H, d, J=7.0 Hz), 5.41 (1H, d, J=6.6 Hz), 5.25 (1H, d, J=4.4 Hz), 4.59(1H, q, J=6.2 Hz), 4.12-4.03 (2H, m), 3.23-3.19 (1H, m), 3.13 (1H, dd,J=8.1, 5.1 Hz), 3.05 (2H, q, J=7.5 Hz), 1.29 (3H, t, J=7.3 Hz). LCMS(ESI) m/z 505.3 [M+H]⁺.

Example 834-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of triisopropyl(thiochroman-8-ylethynyl)silane

The title compound was obtained as in step 2 of Example 76, except that8-iodothiochroman was used in place of 5-(benzyloxy)-2-bromopyrimidine.

¹H-NMR (CDCl₃) δ: 7.27-7.25 (1H, m), 6.97-6.93 (1H, m), 6.89 (1H, t,J=7.6 Hz), 3.07-3.04 (2H, m), 2.80 (2H, t, J=6.1 Hz), 2.12-2.06 (2H, m),1.26-1.04 (21H, m).

Step 2: Synthesis of 8-ethynyl thiochroman

The title compound was obtained as in step 3 of Example 76, except thattriisopropyl(thiochroman-8-ylethynyl)silane was used in place of5-(benzyloxy)-2-((triisopropylsilyl) ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.31-7.26 (1H, m), 7.02-6.98 (1H, m), 6.92 (1H, t,J=7.6 Hz), 3.45 (1H, s), 3.09-3.06 (2H, m), 2.82 (2H, t, J=6.1 Hz),2.13-2.07 (2H, m).

Step 3: Synthesis of 8-ethynyl thiochroman 1,1-dioxide

1,4-Dioxane (1 mL) and water (0.50 mL) were added to 8-ethynylthiochroman (59 mg, 0.34 mmol). Then, oxone (420 mg, 0.68 mmol) wasadded thereto under ice-cooling, and the resulting mixture was allowedto warm to room temperature overnight. The reaction solution waspartitioned at room temperature with the addition of ethyl acetate, asaturated aqueous sodium hydrogen carbonate solution, and water, and theaqueous layer was extracted with ethyl acetate. The organic layer waswashed with saturated saline, and dried over sodium sulfate, followed byfiltration and concentration. The residue was purified by silica gelcolumn chromatography (developing solvent: ethyl acetate/hexane),thereby obtaining the title compound (51 mg, 0.25 mmol, 73%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 7.55 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=7.8 Hz), 7.21(1H, dd, J=7.8, 1.0 Hz), 3.59 (1H, s), 3.44-3.41 (2H, m), 3.01 (2H, t,J=6.2 Hz), 2.48-2.42 (2H, m). LCMS (ESI) m/z 207 [M+H]⁺

Step 4: Synthesis of Example Compound 83

The title compound was obtained as in step 4 of Example 1, except that8-ethynyl thiochroman 1,1-dioxide was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.69 (1H, s), 7.57 (1H, d, J=7.6 Hz),7.48 (1H, t, J=7.6 Hz), 7.30 (1H, d, J=7.6 Hz), 5.87 (1H, d, J=6.8 Hz),4.83-4.79 (1H, m), 4.32-4.30 (1H, m), 4.27-4.25 (1H, m), 3.54-3.51 (2H,m), 3.43-3.33 (2H, m), 3.07 (2H, t, J=6.0 Hz), 2.43-2.38 (2H, m). LCMS(ESI) m/z 549 [M+H]⁺.

Example 842-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-fluoro-benzenesulfonamideStep 1: Synthesis of 3-fluoro-2-((trimethylsilyl) ethynyl)benzenesulfonamide

The title compound was obtained as in step 2 of Example 76, except that3-fluoro-2-iodobenzenesulfonamide and ethynyltrimethylsilane were usedin place of 5-(benzyloxy)-2-bromopyrimidine andethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.85 (1H, d, J=7.8 Hz), 7.45-7.41 (1H, m), 7.31-7.27(1H, m), 5.24 (2H, s), 0.33 (9H, s). LCMS (ESI) m/z 272 [M+H]⁺

Step 2: Synthesis of 2-ethynyl-3-fluorobenzenesulfonamide

The title compound was obtained as in step 3 of Example 76, except that3-fluoro-2-((trimethylsilyl)ethynyl)benzenesulfonamide was used in placeof 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.88 (1H, d, J=7.8 Hz), 7.52-7.47 (1H, m), 7.37-7.31(1H, m), 5.21 (2H, s), 3.90 (1H, s). LCMS (ESI) m/z 200 [M+H]⁺

Step 3: Synthesis of Example Compound 84

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-3-fluorobenzenesulfonamide was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD3OD) δ: 8.30 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.74 (1H, s),7.54-7.49 (1H, m), 7.46-7.41 (1H, m), 5.88 (1H, d, J=6.8 Hz), 4.84-4.81(1H, m), 4.33-4.30 (1H, m), 4.27-4.25 (1H, m), 3.43-3.33 (2H, m). LCMS(ESI) m/z 542 [M+H]⁺.

Example 854-Amino-5-[2-(2-cyano-6-fluoro-phenyl)ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 3-fluoro-2-((trimethylsilyl) ethynyl)benzonitrile

The title compound was obtained as in step 2 of Example 76, except that3-fluoro-2-iodobenzonitrile and ethynyltrimethylsilane were used inplace of 5-(benzyloxy)-2-bromopyrimidine and ethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.46-7.44 (1H, m), 7.41-7.35 (1H, m), 7.33-7.29 (1H,m), 0.31 (9H, s). LCMS (ESI) m/z 218 [M+H]⁺

Step 2: Synthesis of 2-ethynyl-3-fluorobenzonitrile

The title compound was obtained as in step 3 of Example 76, except that3-fluoro-2-((trimethylsilyl)ethynyl)benzonitrile was used in place of5-(benzyloxy)-2-((triisopropylsilyl) ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.51 (1H, dd, J=7.7, 1.5 Hz), 7.49-7.44 (1H, m),7.39-7.35 (1H, m), 3.72 (1H, s).

Step 3: Synthesis of Example Compound 85

The title compound was obtained as in step 4 of Example 1, except that2-ethynyl-3-fluorobenzonitrile was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.27 (1H, s), 7.79 (1H, s), 7.66-7.64 (1H, m),7.57-7.53 (2H, m), 5.88 (1H, d, J=6.8 Hz), 4.84-4.80 (1H, m), 4.33-4.31(1H, m), 4.28-4.26 (1H, m), 3.45-3.35 (2H, m). LCMS (ESI) m/z 488[M+H]⁺.

Example 864-Amino-5-[2-[2-(cyclopropylmethoxy)-6-fluoro-phenyl]ethynyl]-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene

3-Fluoro-2-iodophenol (200 mg, 0.84 mmol) was dissolved intetrahydrofuran (2 mL). Then, cyclopropylmethanol (0.14 mL, 1.7 mmol)and triphenylphosphine (440 mg, 1.7 mmol) were added thereto at roomtemperature, and diisopropyl azodicarboxylate (0.33 ml, 1.7 mmol) wasadded thereto in an ice bath, followed by stirring for 2 hours in an icebath. The reaction solution was concentrated, and the residue waspurified by silica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene (192 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.26-7.19 (1H, m), 6.72-6.67 (1H, m), 6.57 (1H, d,J=8.3 Hz), 3.91 (2H, d, J=6.6 Hz), 1.33-1.28 (1H, m), 0.68-0.63 (2H, m),0.44-0.41 (2H, m).

Step 2: Synthesis of((2-(cyclopropylmethoxy)-6-fluorophenyl)ethynyl)trimethylsilane

The title compound was obtained as in step 2 of Example 76, except that1-(cyclopropylmethoxy)-3-fluoro-2-iodobenzene and ethynyltrimethylsilanewere used in place of 5-(benzyloxy)-2-bromopyrimidine andethynyltriisopropylsilane.

¹H-NMR (CDCl₃) δ: 7.17 (1H, dt, J=6.6, 8.4 Hz), 6.69-6.64 (1H, m), 6.61(1H, d, J=8.5 Hz), 3.91 (2H, d, J=6.3 Hz), 1.31-1.24 (1H, m), 0.64-0.60(2H, m), 0.45-0.41 (2H, m), 0.28 (9H, s).

Step 3: Synthesis of 1-(cyclopropylmethoxy)-2-ethynyl-3-fluorobenzene

The title compound was obtained as in step 3 of Example 76, except that((2-(cyclopropylmethoxy)-6-fluorophenyl)ethynyl)trimethylsilane was usedin place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.24 (1H, dt, J=6.6, 8.4 Hz), 6.72 (1H, t, J=8.4 Hz),6.67 (1H, J=8.4 Hz), 3.93 (2H, d, J=6.6 Hz), 3.52 (1H, s), 1.36-1.30(1H, m), 0.68-0.63 (2H, m), 0.43-0.39 (2H, m).

Step 4: Synthesis of Example Compound 86

The title compound was obtained as in step 4 of Example 1, except that1-(cyclopropylmethoxy)-2-ethynyl-3-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.25 (1H, s), 7.59 (1H, s), 7.33-7.27 (1H, m), 6.88(1H, d, J=8.5 Hz), 6.79 (1H, t, J=8.5 Hz), 5.88 (1H, d, J=7.0 Hz),4.86-4.83 (1H, m), 4.34-4.32 (1H, m), 4.28-4.26 (1H, m), 4.01 (2H, d,J=7.0 Hz), 3.44-3.34 (2H, m), 1.40-1.32 (1H, m), 0.73-0.68 (2H, m), 0.43(2H, m). LCMS (ESI) m/z 533 [M+H]⁺.

Example 874-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-[4-(3-pyridylmethoxy)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (500 mg, 0.82 mmol), ethynyltrimethylsilane (240 mg, 2.5mmol), bis(triphenylphosphine)palladium (II) dichloride (58 mg, 0.082mmol), copper iodide (16 mg, 0.082 mmol), and diisopropylethylamine(0.28 mL, 1.6 mmol) were suspended in tetrahydrofuran (5 mL). Thereaction solution was stirred at 70° C. overnight and filtered through acelite bed, followed by distilling off the solvent. The residue waspurified by silica gel column chromatography (developing solvent:methanol/chloroform), thereby obtaining the title compound (339 mg, 0.58mmol, 71%) as a yellow amorphous substance.

¹H-NMR (CDCl₃) δ: 9.41 (1H, brs), 8.50 (1H, s), 7.16 (1H, s), 5.98 (2H,brs), 5.63 (1H, d, J=4.6 Hz), 5.25-5.21 (1H, m), 5.07-5.03 (1H, m),4.51-4.49 (1H, m), 3.59-3.50 (2H, m), 1.59 (3H, s), 1.43 (9H, s), 1.34(3H, s), 0.26 (9H, s). LCMS (ESI) m/z 581 [M+H]⁺

Step 2: Synthesis of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (339 mg, 0.58 mmol) was dissolved in tetrahydrofuran (6.8 mL),and a tetrabutylammonium fluoride solution (1 M tetrahydrofuransolution, 0.70 mL, 0.70 mmol) was added thereto at room temperature,followed by stirring at room temperature for 25 minutes. After thesolvent was distilled off, the residue was purified by silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the title compound (260 mg, 0.51 mmol, 88%) as a yellowpowder.

¹H-NMR (CDCl₃) δ: 9.25 (1H, brs), 8.51 (1H, s), 7.20 (1H, s), 6.11 (2H,brs), 5.65 (1H, d, J=4.6 Hz), 5.29-5.25 (1H, m), 5.10-5.06 (1H, m),4.52-4.49 (1H, m), 3.66-3.53 (2H, m), 3.25 (1H, s), 1.61 (3H, s), 1.44(9H, s), 1.35 (3H, s). LCMS (ESI) m/z 509 [M+H]⁺

Step 3: Synthesis of Example Compound 87

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (20 mg, 0.039 mmol), 3-((4-iodophenoxy)methyl)pyridine (24 mg,0.079 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg,0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), anddiisopropylethylamine (0.013 mL, 0.079 mmol) were suspended intetrahydrofuran (0.30 mL). The reaction solution was stirred at 70° C.overnight, and a mixed solution (0.60 mL) of trifluoroaceticacid/water=4/1 was added thereto at room temperature, followed bystirring at room temperature overnight. After the solvent was distilledoff, the residue was purified by basic silica gel column chromatography(developing solvent: methanol/chloroform), thereby obtaining the titlecompound (2.1 mg, 0.0039 mmol, 10%) as a yellow powder.

¹H-NMR (CD₃OD) δ: 8.65-8.60 (1H, m), 8.55-8.50 (1H, m), 8.24 (1H, s),7.95-7.90 (1H, m), 7.50-7.40 (4H, m), 7.05-7.00 (2H, brs), 5.84-5.82(1H, brs), 5.19 (2H, s), 4.80-4.70 (1H, m), 4.35-4.20 (2H, m), 3.40-3.30(2H, m). LCMS (ESI) m/z 552 [M+H]⁺.

Example 884-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(3-fluoro-2-pyridyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 3 of Example 87, except that3-fluoro-2-iodopyridine was used in place of3-((4-iodophenoxy)methyl)pyridine.

¹H-NMR (CD₃OD) δ: 8.43-8.39 (1H, m), 8.26 (1H, s), 7.78 (1H, s),7.78-7.71 (1H, m), 7.50-7.46 (1H, m), 5.88 (1H, d, J=7.1 Hz), 4.90-4.60(1H, m), 4.33-4.31 (1H, m), 4.28-4.25 (1H, m), 3.40-3.31 (2H, m). LCMS(ESI) m/z 464 [M+H]⁺.

Example 894-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-methylsulfanylphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 3 of Example 87, except that(2-iodophenyl)(methyl)sulfane was used in place of3-((4-iodophenoxy)methyl)pyridine.

¹H-NMR (CD₃OD) δ: 8.24 (1H, s), 7.62 (1H, s), 7.48-7.46 (1H, m),7.37-7.34 (2H, m), 7.22-7.16 (1H, m), 5.86 (1H, d, J=8.0 Hz), 4.83-4.81(1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H, m), 2.55(3H, s). LCMS (ESI) m/z 491 [M+H]⁺.

Example 902-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]benzenesulfonamide

The title compound was obtained as in step 3 of Example 87, except that2-iodobenzenesulfonamide was used in place of3-((4-iodophenoxy)methyl)pyridine.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 8.02 (1H, dd, J=8.0, 4.0 Hz), 7.74 (1H,dd, J=7.8, 4.0 Hz), 7.71 (1H, s), 7.85-7.56 (1H, m), 7.53-7.49 (1H, m),5.87 (1H, d, J=6.8 Hz), 4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25(1H, m), 3.40-3.35 (2H, m). LCMS (ESI) m/z 524 [M+H]⁺.

Example 913-[[4-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]phenoxy]methyl]benzamide

The title compound was obtained as in step 3 of Example 87, except that3-((4-iodophenoxy)methyl)benzamide was used in place of3-((4-iodophenoxy)methyl)pyridine.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J=8.1 Hz),7.65 (1H, d, J=8.0 Hz), 7.54 (1H, s), 7.54-7.49 (1H, m), 7.48 (2H, d,J=8.0 Hz), 7.05 (2H, d, J=8.0 Hz), 5.85 (1H, d, J=7.1 Hz), 5.19 (2H, s),4.83-4.81 (1H, m), 4.33-4.29 (1H, m), 4.27-4.25 (1H, m), 3.40-3.35 (2H,m). LCMS (ESI) m/z 594 [M+H]⁺.

Example 924-[2-[4-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]isoquinoline

The title compound was obtained as in step 3 of Example 87, except that4-iodoisoquinoline was used in place of3-((4-iodophenoxy)methyl)pyridine.

¹H-NMR (CD₃OD) δ: 9.20 (1H, s), 8.69 (1H, s), 8.34 (1H, d, J=8.3 Hz),8.26 (1H, s), 8.16 (1H, d, J=8.3 Hz), 7.95-7.90 (1H, m), 7.81 (1H, s),7.80-7.74 (1H, m), 5.92 (1H, d, J=6.8 Hz), 4.87-4.81 (1H, m), 4.36-4.33(1H, m), 4.29-4.25 (1H, m), 3.43-3.39 (2H, m). LCMS (ESI) m/z 496[M+H]⁺.

Example 934-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanoland(4aR,6R,7S,7aR)-6-amino-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol

(1R,2S,3R,5R)-3-Amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride (40 g, 218 mmol) was dissolved at room temperature inmethanol (400 mL) and 2,2-dimethoxypropane (54 mL, 436 mmol), andmethanesulfonic acid (14 mL, 218 mmol) was added thereto dropwise in anice bath with stirring so as to keep the internal temperature at 7° C.or lower. After the mixture was stirred in an ice bath for 5 minutes andat room temperature overnight, triethylamine (122 mL, 872 mmol) wasadded thereto dropwise in an ice bath so as to keep the internaltemperature at 10° C. or lower. After the mixture was stirred in an icebath for 5 minutes and at room temperature for 30 minutes, the solventwas distilled off under reduced pressure, thereby obtaining the titlecompound as a crude isomeric mixture (102 g).

LCMS (ESI) m/z 188 [M+H]⁺

Step 2: Synthesis of((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanoland(4aR,6R,7S,7aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol

The crude isomeric mixture (102 g) of((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanoland(4aR,6R,7S,7aR)-6-amino-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-olobtained in step 1 of Example 93, and2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (46 g, 240 mmol) wassuspended in 2-butanol (400 mL). Then, triethylamine (61 mL, 436 mmol)was added thereto at room temperature, and the reaction solution wasstirred at 80° C. overnight. After the reaction solvent was distilledoff under reduced pressure, the residue was partitioned with theaddition of ethyl acetate and an aqueous sodium hydrogen carbonatesolution, followed by extraction with ethyl acetate. The organic layerwas washed with saturated saline, and dried over sodium sulfate,followed by distilling off the solvent, thereby obtaining the titlecompound as a crude isomeric mixture (72 g).

LCMS (ESI) m/z 324 [M+H]⁺

Step 3: Synthesis of((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

The crude isomeric mixture (72 g) of((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanoland(4aR,6R,7S,7aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxin-7-ol,obtained in step 2 of Example 93, was suspended in acetone (720 mL), andmethanesulfonic acid (14.2 mL, 218 mmol) was added thereto in an icebath. After the reaction solution was stirred in an ice bath for 40minutes and at room temperature overnight, triethylamine (122 mL, 872mmol) was added thereto dropwise in an ice bath so as to keep theinternal temperature at 10° C. or lower. After the mixture was stirredin an ice bath for 10 minutes and at room temperature for 30 minutes,the solvent was distilled off under reduced pressure. The residue waspartitioned with the addition of ethyl acetate and a sodium bicarbonatesolution, followed by extraction with ethyl acetate. The organic layerwas washed with saturated saline, and dried over sodium sulfate. Thesolvent was distilled off, thereby giving a crude product of the titlecompound (77 g) as a brown oil.

¹H-NMR (CDCl₃) δ: 8.63 (1H, s), 7.33 (1H, d, J=3.7 Hz), 6.63 (1H, d,J=3.7 Hz), 5.03-4.95 (2H, m), 4.73-4.70 (1H, m), 3.90-3.86 (1H, m),3.83-378 (1H, m), 2.52-2.43 (2H, m), 2.38-2.32 (1H, m), 2.18-2.16 (1H,m), 1.60 (3H, s), 1.32 (3H, s). LCMS (ESI) m/z 324 [M+H]⁺

Step 4: Synthesis of7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The crude product (77 g), i.e.,((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol,obtained in step 3 of Example 93 was dissolved in N,N-dimethylformamide(770 mL). Then, imidazole (37 g, 545 mmol) was added thereto at roomtemperature, and tert-butyldimethylchlorosilicane (58 g, 382 mmol) wasadded in a water bath (25° C.), followed by stirring for 40 minutes in awater bath (29° C.). The reaction solution was partitioned with theaddition of ethyl acetate (800 mL) and water (800 mL) in an ice bath,and the organic layer was washed with water (400 mL). After the aqueouslayer (about 300 mL) was removed, saturated saline (100 mL) was added tothe organic layer and washed, followed by further washing with saturatedsaline (400 mL). After the resulting product was dried over sodiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (developingsolvent: ethyl acetate/hexane), thereby obtaining the title compound (79g, four steps: 83%) as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.62 (1H, s), 7.31 (1H, d, J=3.7 Hz), 6.63 (1H, d,J=3.7 Hz), 5.09-5.04 (1H, m), 4.88 (1H, t, J=6.3 Hz), 4.67-4.64 (1H, m),3.82-3.74 (2H, m), 2.39-2.37 (3H, m), 1.59 (3H, s), 1.31 (3H, s), 0.93(9H, s), 0.087 (3H, s), 0.074 (3H, s). LCMS (ESI) m/z 438 [M+H]⁺

Step 5: Synthesis of7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

7-((3aS,4R,6R,6aR)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine(79 g, 180 mmol) was dissolved in N,N-dimethylformamide (790 mL), andN-iodosuccinimide (45 g, 198 mmol) was added thereto at roomtemperature, followed by stirring at 50° C. for 11 hours and at roomtemperature for 12 hours. Ethyl acetate (600 mL), a saturated sodiumhydrogen sulphite solution (300 mL), and water (600 mL) were added in anice bath to the reaction solution, followed by stirring at roomtemperature for 10 minutes. After partition, the organic layer wassequentially washed with a liquid mixture of water (600 mL) andsaturated saline (100 mL), and saturated saline (500 mL). After theresulting product was dried over sodium sulfate, the solvent wasdistilled off under reduced pressure, thereby giving a crude product ofthe title compound (95 g) as a brown oil.

¹H-NMR (CDCl₃) δ: 8.61 (1H, s), 7.46 (1H, s), 5.08-5.04 (1H, m), 4.85(1H, t, J=6.3 Hz), 4.64-4.62 (1H, m), 3.81-3.73 (2H, m), 2.42-2.32 (3H,m), 1.58 (3H, s), 1.30 (3H, s), 0.94 (9H, s), 0.095 (3H, s), 0.082 (3H,s). LCMS (ESI) m/z 564 [M+H]⁺

Step 6: Synthesis of((3aR,4R,6R,6aS)-6-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

The crude product (95 g), i.e.,7-((3aS,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine,obtained in step 5 of Example 93 was dissolved in tetrahydrofuran (950mL), and a tetrabutylammonium fluoride solution (1 M tetrahydrofuransolution, 180 mL) was added thereto at room temperature, followed bystirring at room temperature for 1 hour. The resulting mixture waspartitioned in an ice bath with the addition of ethyl acetate (500 mL),water (500 mL), and a saturated sodium bicarbonate solution (300 mL),and the aqueous layer was extracted with ethyl acetate (500 mL). Theorganic layer was washed with saturated saline (500 mL), and dried oversodium sulfate, followed by distilling off the solvent under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent: ethyl acetate/hexane), thereby obtaining the titlecompound (70 g, two steps: 86%) as a light-green amorphous substance.

¹H-NMR (CDCl₃) δ: 8.62 (1H, s), 7.48 (1H, s), 5.05-4.99 (1H, m), 4.91(1H, t, J=6.5 Hz), 4.71-4.68 (1H, m), 3.89-3.85 (1H, m), 3.82-3.78 (1H,m), 2.50-2.45 (2H, m), 2.31-2.27 (1H, m), 1.90-1.88 (1H, m), 1.59 (3H,s), 1.31 (3H, s). LCMS (ESI) m/z 450 [M+H]⁺

Step 7: Synthesis of((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

((3aR,4R,6R,6aS)-6-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(70 g) was dissolved in 1,4-dioxane (350 mL), and 28% aqueous ammonia(350 mL) was added thereto at room temperature, followed by stirring at100° C. overnight in a pressure-resistant container. After the solventwas distilled off under reduced pressure, the resulting product wassuspended in water (700 mL), followed by stirring at room temperatureovernight. The precipitate was collected by filtration and washed withwater (420 mL), followed by drying to give the title compound (67 g,99%) as a light-brown powder.

¹H-NMR (CDCl₃) δ: 8.26 (1H, s), 7.12 (1H, s), 5.69-5.67 (2H, brs), 4.94(1H, t, J=6.2 Hz), 4.90-4.84 (1H, m), 4.72-4.70 (1H, m), 3.89-3.85 (1H,m), 3.81-3.77 (1H, m), 3.06-3.04 (1H, brs), 2.58-2.46 (2H, m), 2.35-2.27(1H, m), 1.59 (3H, s), 1.33 (3H, s) LCMS (ESI) m/z 431 [M+H]⁺.

Step 8: Synthesis of7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

((3aR,4R,6R,6aS)-6-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(51 g, 118 mmol) and phthalimide (35 g, 236 mmol) were dissolved intetrahydrofuran (1000 mL). Then, triphenylphosphine (93 g, 354 mmol) wasadded thereto with stirring under ice-cooling. After triphenylphosphinewas dissolved, diisopropyl azodicarboxylate (70 mL, 354 mmol) was addedthereto dropwise with stirring under ice-cooling. After the reactionsolution was stirred for 30 minutes under ice-cooling, the resultingproduct was stirred at room temperature for 90 minutes, and the reactionsolution was distilled off under reduced pressure. Ethanol (750 mL),hydrazine monohydrate (25 mL, 519 mmol), and water (150 mL) were addedto the residue, followed by stirring at 80° C. overnight. After thesolvent was distilled off under reduced pressure, the resulting productwas partitioned with the addition of chloroform, water, and a saturatedaqueous sodium hydrogen carbonate solution. The aqueous layer was thenseparated and extracted with chloroform. All of the organic layers werecombined and dried over sodium sulfate, followed by distilling off thesolvent. The residue was purified by basic silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the title compound (52 g, 89 wt %) as a yellow amorphoussubstance.

¹H-NMR (CDCl₃) δ: 8.27 (1H, s), 7.13 (1H, s), 5.62-5.60 (2H, brs),4.96-4.90 (2H, m), 4.56 (1H, t, J=6.0 Hz), 2.90 (2H, d, J=6.6 Hz),2.46-2.40 (1H, m), 2.27-2.21 (1H, m), 2.17-2.08 (1H, m), 1.58 (3H, s),1.32 (3H, s). LCMS (ESI) m/z 430 [M+H]⁺.

Step 9: Synthesis of tert-butylN-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate

7-((3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine(51.5 g, 89 wt %, ca. 107 mmol) obtained in step 8 of Example 93 wasdissolved in acetonitrile (515 mL). Then,1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido:1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: OrganicLetters, 2012, 10, 2626-2629) (70.5 g, 160 mmol) was added thereto atroom temperature. After the reaction solution was stirred at roomtemperature for 30 minutes, water (1030 mL) and a saturated aqueousammonium chloride solution (258 mL) were added to the reaction solution,followed by stirring at room temperature for 5 hours. The precipitatewas collected by filtration and washed with water (1545 mL), followed bydrying to give the title compound (57.1 g, 88%) as a yellowish whitepowder.

¹H-NMR (CDCl₃) δ: 8.33 (1H, s), 7.05 (1H, s), 6.62-6.60 (1H, brs),5.73-5.71 (2H, brs), 4.99 (1H, t, J=5.9 Hz), 4.78-4.72 (1H, m),4.64-4.62 (1H, m), 3.36-3.32 (1H, m), 3.24-3.25 (1H, m), 2.57-2.46 (2H,m), 2.38-2.32 (1H, m), 1.56 (3H, s), 1.48 (9H, s), 1.29 (3H, s). LCMS(ESI) m/z 609 [M+H]⁺.

Step 10: Synthesis of Example Compound 93

tert-ButylN-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)sulfamoyl carbamate (20 mg, 0.033 mmol), 1-ethynylnaphthalene (10 mg,0.066 mmol), bis(triphenylphosphine)palladium (II) dichloride (3 mg,0.0043 mmol), copper iodide (1 mg, 0.0053 mmol), anddiisopropylethylamine (0.011 mL, 0.066 mmol) were suspended intetrahydrofuran (0.30 mL). After the reaction solution was stirred at70° C. for 1 hour, a mixed solution (0.60 mL) of trifluoroaceticacid/water=4/1 was added thereto at room temperature, followed bystirring at room temperature overnight. After the solvent was distilledoff, the residue was purified by silica gel column chromatography(developing solvent: methanol/chloroform), thereby obtaining the titlecompound (8.2 mg, 50%) as a yellow powder.

¹H-NMR (CD₃OD) δ: 8.36 (1H, d, J=8.5 Hz), 8.17 (1H, s), 7.93-7.89 (2H,m), 7.78-7.75 (1H, m), 7.74 (1H, s), 7.64-7.47 (3H, m), 5.02-4.95 (1H,m), 4.47-4.44 (1H, m), 4.05-4.03 (1H, m), 3.30-3.16 (2H, m), 2.52-2.44(1H, m), 2.37-2.28 (1H, m), 1.90-1.82 (1H, m). LCMS (ESI) m/z 493[M+H]⁺.

Example 944-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2,6-dimethoxyphenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that2-ethynyl-1,3-dimethoxybenzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.52 (1H, s), 7.27 (1H, t, J=8.5 Hz),6.68 (2H, d, J=8.5 Hz), 4.95-4.86 (1H, m), 4.40-4.35 (1H, m), 4.05-3.95(1H, m), 3.91 (6H, s), 3.30-3.13 (2H, m), 2.50-2.40 (1H, m), 2.34-2.28(1H, m), 1.85-1.73 (1H, m). LCMS (ESI) m/z 503 [M+H]⁺.

Example 954-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that2-ethynyl-1-fluoro-3-methoxybenzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.59 (1H, s), 7.34-7.28 (1H, m), 6.88(1H, d, J=8.5 Hz), 6.78-6.74 (1H, m), 4.97-4.86 (1H, m), 4.43-4.39 (1H,m), 4.03-4.00 (1H, m), 3.96 (3H, s), 3.30-3.23 (1H, m), 3.22-3.14 (1H,m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.85-1.73 (1H, m). LCMS (ESI)m/z 491 [M+H]⁺.

Example 968-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]quinoline

The title compound was obtained as in step 10 of Example 93, except that8-ethynylquinoline was used in place of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 9.04-9.02 (1H, m), 8.40-8.35 (1H, m), 8.16 (1H, s),7.94-7.85 (2H, m), 7.63 (1H, s), 7.61-7.57 (2H, m), 5.00-4.91 (1H, m),4.46-4.42 (1H, m), 4.05-4.00 (1H, m), 3.30-3.14 (2H, m), 2.50-2.38 (1H,m), 2.34-2.28 (1H, m), 1.87-1.81 (1H, m). LCMS (ESI) m/z 494 [M+H]⁺.

Example 974-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine Step 1

The title compound was obtained as in step 10 of Example 93, Except that1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.14 (1H, s), 7.60 (1H, s), 7.32-7.26 (1H, m), 6.86(1H, d, J=8.5 Hz), 6.79-6.74 (1H, m), 5.00-4.91 (1H, m), 4.45-4.42 (1H,m), 4.23 (2H, q, J=7.1 Hz), 4.05-4.00 (1H, m), 3.30-3.24 (1H, m),3.21-3.15 (1H, m), 2.50-2.40 (1H, m), 2.34-2.28 (1H, m), 1.87-1.81 (1H,m), 1.47 (3H, t, J=7.1 Hz). LCMS (ESI) m/z 505 [M+H]⁺.

Step 2: Synthesis of4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine hydrochloride

The title compound hydrochloride was obtained in accordance with step 5of Example 1.

¹H-NMR (CD₃OD) δ: 8.32 (1H, s), 7.95 (1H, s), 7.38-7.34 (1H, m), 6.93(1H, d, J=8.5 Hz), 6.84-6.80 (1H, m), 5.13-5.09 (1H, m), 4.41-4.37 (1H,m), 4.27 (2H, q, J=7.0 Hz), 4.02-4.00 (1H, m), 3.28-3.23 (1H, m),3.19-3.13 (1H, m), 2.47-2.42 (1H, m), 2.32-2.80 (1H, m), 1.87-1.79 (1H,m), 1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 505 [M+H]⁺

Example 984-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that2-ethynyl-1-fluoro-3-methylsulfanyl-benzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.15 (1H, s), 7.67 (1H, s), 7.35-7.30 (1H, m), 7.10(1H, d, J=7.8 Hz), 6.98-6.92 (1H, m), 5.00-4.91 (1H, m), 4.45-4.40 (1H,m), 4.05-4.00 (1H, m), 3.30-3.24 (1H, m), 3.21-3.15 (1H, m), 2.56 (3H,s), 2.50-2.41 (1H, m), 2.34-2.28 (1H, m), 1.87-1.78 (1H, m). LCMS (ESI)m/z 507 [M+H]⁺.

Example 994-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfanyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that1-ethylsulfanyl-2-ethynyl-3-fluoro-benzene was used in place of1-ethynylnaphthalene.

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, s), 7.93 (1H, s), 7.42-7.36 (1H, m), 7.23(1H, d, J=8.8 Hz), 7.13 (1H, t, J=8.8 Hz), 6.65 (1H, dd, J=6.6, 5.9 Hz),6.53 (2H, brs), 4.90 (1H, ddd, J=10.3, 9.9, 8.4 Hz), 4.71 (1H, brs),4.24 (1H, dd, J=8.8, 5.5 Hz), 3.79 (1H, dd, J=5.5, 3.7 Hz), 3.10-3.05(1H, m), 3.09 (2H, q, J=7.3 Hz), 2.96-2.89 (1H, m), 2.22 (1H, dt,J=13.2, 8.1 Hz), 2.15-2.06 (1H, m), 1.61-1.53 (1H, m), 1.30 (3H, t,J=7.3 Hz). LCMS (ESI) m/z 521 [M+H]⁺.

Example 1004-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethoxy-6-methoxy-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that1-ethoxy-2-ethynyl-3-methoxybenzene was used in place of1-ethynylnaphthalene.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.72 (1H, s), 7.27 (1H, t, J=8.4 Hz),6.72-6.65 (3H, m), 6.53 (2H, s), 4.92-4.85 (2H, m), 4.68 (1H, d, J=4.4Hz), 4.25-4.20 (1H, m), 4.16 (2H, q, J=7.0 Hz), 3.87 (3H, s), 3.82-3.78(1H, m), 3.12-3.06 (1H, m), 2.96-2.90 (1H, m), 2.23-2.18 (1H, m),2.15-2.07 (1H, m), 1.61-1.53 (1H, m), 1.37 (3H, t, J=7.0 Hz). LCMS (ESI)m/z 517.3 [M+H]⁺.

Example 1014-[4-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3,5-difluoro-phenyl]morpholine

The title compound was obtained as in step 10 of Example 93, except that4-(4-ethynyl-3,5-difluorophenyl)morpholine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.14 (1H, s), 7.59 (1H, s), 6.63 (2H, d, J=11.5 Hz),4.97-4.93 (1H, m), 4.41 (1H, dd, J=8.4, 5.7 Hz), 4.01 (1H, dd, J=5.7,3.8 Hz), 3.80 (4H, t, J=4.9 Hz), 3.27-3.11 (6H, m), 2.48-2.40 (1H, m),2.35-2.25 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m/z 564 [M+H]⁺.

Example 1024-Amino-5-[2-[2,6-difluoro-4-(1-piperidyl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidine

The title compound was obtained as in step 1 of Example 23, except thatpiperidine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.34 (2H, d, J=11.4 Hz), 3.37 (1H, s), 3.26-3.20 (4H,m), 1.68-1.60 (6H, m). LCMS (ESI) m/z 222 [M+H]⁺

Step 2: Synthesis of Example Compound 102

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3,5-difluorophenyl)piperidine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.57 (1H, s), 6.54 (2H, d, J=11.7 Hz),4.98-4.91 (1H, m), 4.40 (1H, dd, J=8.4, 5.6 Hz), 4.01 (1H, dd, J=5.6,3.8 Hz), 3.31-3.30 (4H, m), 3.28-3.14 (2H, m), 2.48-2.39 (1H, m),2.35-2.26 (1H, m), 1.85-1.75 (1H, m), 1.70-1.63 (6H, m). LCMS (ESI) m/z562 [M+H]⁺.

Example 1034-Amino-5-[2-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)-4-methylpiperazine

The title compound was obtained as in step 1 of Example 23, except that4-methylpiperazine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.36 (2H, d, J=11.0 Hz), 3.39 (1H, s), 3.27-3.23 (4H,m), 2.54-2.50 (4H, m), 2.34 (3H, s). LCMS (ESI) m/z 237 [M+H]⁺

Step 2: Synthesis of Example Compound 103

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3,5-difluorophenyl)-4-methylpiperazine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.76 (1H, s), 6.76 (2H, d, J=10.6 Hz),5.06-4.97 (1H, m), 4.40 (1H, dd, J=8.6, 5.6 Hz), 4.01 (1H, dd, J=5.6,3.7 Hz), 3.49-3.11 (10H, m), 2.97 (3H, s), 2.48-2.40 (1H, m), 2.34-2.26(1H, m), 1.87-1.77 (1H, m). LCMS (ESI) m/z 577 [M+H]⁺.

Example 1044-Amino-5-[2-[2,6-difluoro-4-(pyrazol-1-ylmethoxy)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of4-((1H-pyrazol-1-yl)methoxy)-2,6-difluorobenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that2,6-difluoro-4-hydroxybenzaldehyde and 1-(chloromethyl)pyrazolehydrochloride were used in place of 2-fluoro-6-hydroxybenzaldehyde andiodoethane.

¹H-NMR (CDCl₃) δ: 10.20 (1H, s), 7.65-7.62 (2H, m), 6.81 (2H, d, J=10.0Hz), 6.39 (1H, t, J=2.1 Hz), 6.05 (2H, s). LCMS (ESI) m/z 239 [M+H]⁺

Step 2: Synthesis of1-((4-ethynyl-3,5-difluorophenoxy)methyl)-1H-pyrazole

The title compound was obtained as in step 1 of Example 51, except that4-((1H-pyrazol-1-yl)methoxy)-2,6-difluorobenzaldehyde was used in placeof 2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.64-7.60 (2H, m), 6.73 (2H, d, J=8.8 Hz), 6.37 (1H,t, J=2.2 Hz), 5.99 (2H, s), 3.42 (1H, s). LCMS (ESI) m/z 235 [M+H]⁺

Step 3: Synthesis of Example Compound 104

The title compound was obtained as in step 10 of Example 93, except that1-((4-ethynyl-3,5-difluorophenoxy)methyl)-1H-pyrazole was used in placeof 1-ethynylnaphthalene.

¹H-NMR (DMSO-D₆) δ: 8.14 (1H, s), 8.04 (1H, d, J=2.0 Hz), 7.91 (1H, s),7.61 (1H, d, J=1.5 Hz), 7.15 (2H, d, J=9.5 Hz), 6.64 (1H, t, J=6.3 Hz),6.51 (2H, s), 6.37-6.36 (1H, m), 6.18 (2H, s), 4.91-4.86 (2H, m),4.69-4.66 (1H, brs), 4.23-4.19 (1H, m), 3.80-3.77 (1H, brs), 3.09-3.04(1H, m), 2.95-2.88 (1H, m), 2.26-2.18 (1H, m), 2.14-2.10 (1H, m),1.59-1.51 (1H, m). LCMS (ESI) m/z 575 [M+H]⁺.

Example 1054-Amino-5-[2-(2,6-difluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine

The title compound was obtained as in step 1 of Example 23, except thatpyrrolidine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.02 (2H, d, J=10.6 Hz), 3.38 (1H, s), 3.28-3.22 (4H,m), 2.04-2.00 (4H, m). LCMS (ESI) m/z 208 [M+H]⁺

Step 2: Synthesis of Example Compound 105

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3,5-difluorophenyl)pyrrolidine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.54 (1H, s), 6.21 (2H, d, J=11.0 Hz),4.40 (1H, dd, J=8.6, 5.7 Hz), 4.00 (1H, t, J=4.6 Hz), 3.67-3.62 (1H, m),3.29-3.05 (6H, m), 2.48-2.39 (1H, m), 2.35-2.25 (1H, m), 2.08-2.02 (4H,m), 1.85-1.75 (1H, m). LCMS (ESI) m/z 548 [M+H]⁺.

Example 1064-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-[2-ethoxy-6-fluoro-4-(1-piperidyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(3-ethoxy-4-ethynyl-5-fluorophenyl)piperidine

The title compound was obtained as in step 1 of Example 34, except that1-(4-ethynyl-3,5-difluorophenyl)piperidine was used in place of4-(4-ethynyl-3,5-difluorophenyl)morpholine.

¹H-NMR (CDCl₃) δ: 6.24 (1H, dd, J=12.8, 2.2 Hz), 6.18-6.16 (1H, m), 4.12(2H, q, J=7.0 Hz), 3.42 (1H, s), 3.27-3.22 (4H, m), 1.73-1.60 (6H, m),1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 248 [M+H]⁺

Step 2: Synthesis of Example Compound 106

The title compound was obtained as in step 10 of Example 93, except that1-(3-ethoxy-4-ethynyl-5-fluorophenyl)piperidine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.50 (1H, s), 6.33-6.30 (2H, m),4.97-4.90 (1H, m), 4.39 (1H, dd, J=8.4, 5.5 Hz), 4.17 (2H, q, J=7.1 Hz),4.00 (1H, dd, J=5.7, 3.8 Hz), 3.29-3.13 (6H, m), 2.47-2.40 (1H, m),2.34-2.26 (1H, m), 1.84-1.75 (1H, m), 1.71-1.61 (6H, m), 1.45 (3H, t,J=7.1 Hz). LCMS (ESI) m/z 588 [M+H]⁺.

Example 1074-Amino-5-[2-(4-benzyloxy-2,6-difluoro-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-(benzyloxy)-2,6-difluorobenzaldehyde

The title compound was obtained as in step 1 of Example 55, except that2,6-difluoro-4-hydroxybenzaldehyde and benzylbromide were used in placeof 2-fluoro-6-hydroxybenzaldehyde and iodoethane.

¹H-NMR (CDCl₃) δ: 10.20 (1H, s), 7.49-7.36 (5H, m), 6.57 (2H, d, J=10.5Hz), 5.11 (2H, s). LCMS (ESI) m/z 249 [M+H]⁺

Step 2: Synthesis of 5-(benzyloxy)-2-ethynyl-1,3-difluorobenzene

The title compound was obtained as in step 1 of Example 51, except that4-(benzyloxy)-2,6-difluorobenzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.41-7.36 (5H, m), 6.54 (2H, d, J=9.0 Hz), 5.04 (2H,s), 3.42 (1H, s). LCMS (ESI) m/z 245 [M+H]⁺

Step 3: Synthesis of Example Compound 107

The title compound was obtained as in step 10 of Example 93, except that5-(benzyloxy)-2-ethynyl-1,3-difluorobenzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.15 (1H, s), 7.63 (1H, s), 7.45-7.34 (5H, m), 6.78(2H, d, J=9.5 Hz), 5.13 (2H, s), 4.92-4.88 (1H, m), 4.43-4.40 (1H, m),4.02-3.98 (1H, m), 3.30-3.13 (2H, m), 2.46-2.40 (1H, m), 2.31-2.28 (1H,m), 1.83-1.78 (1H, m). LCMS (ESI) m/z 585 [M+H]⁺.

Example 1083-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]-8-oxa-3-azabicyclo[3,2,1]octaneStep 1: Synthesis of3-(4-ethynyl-3,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

The title compound was obtained as in step 1 of Example 23, except that8-oxa-3-azabicyclo[3.2.1]octane was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.28 (2H, dd, J=13.9, 2.9 Hz), 4.52-4.49 (2H, m), 3.40(1H, s), 3.26 (2H, d, J=11.3 Hz), 3.08 (2H, dd, J=11.3, 2.7 Hz),2.04-1.96 (2H, m), 1.89-1.82 (2H, m). LCMS (ESI) m/z 250 [M+H]⁺

Step 2: Synthesis of3-(3-ethoxy-4-ethynyl-5-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane

The title compound was obtained as in step 1 of Example 34, except that3-(4-ethynyl-3,5-difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane wasused in place of 4-(4-ethynyl-3,5-difluorophenyl)morpholine.

¹H-NMR (CDCl₃) δ: 6.12 (1H, dd, J=12.6, 2.4 Hz), 6.03 (1H, s), 4.51-4.47(2H, m), 4.09 (2H, q, J=7.0 Hz), 3.40 (1H, s), 3.28 (2H, d, J=11.3 Hz),3.06 (2H, dd, J=11.3, 2.7 Hz), 2.03-1.92 (2H, m), 1.92-1.84 (2H, m),1.46 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 276 [M+H]⁺

Step 3: Synthesis of Example Compound 108

The title compound was obtained as in step 10 of Example 93, except that3-(3-ethoxy-4-ethynyl-5-fluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octanewas used in place of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.49 (1H, s), 6.29 (1H, d, J=1.8 Hz),6.25 (1H, s), 4.94-4.90 (1H, m), 4.47 (2H, s), 4.39 (1H, dd, J=8.4, 5.9Hz), 4.18 (2H, q, J=7.1 Hz), 4.00 (1H, dd, J=5.7, 3.8 Hz), 3.45 (2H, d,J=11.0 Hz), 3.26 (1H, dd, J=12.8, 6.2 Hz), 3.17 (1H, dd, J=12.6, 6.8Hz), 2.97 (2H, dd, J=11.5, 2.4 Hz), 2.48-2.39 (1H, m), 2.35-2.25 (1H,m), 2.00-1.87 (4H, m), 1.84-1.74 (1H, m), 1.45 (3H, t, J=7.0 Hz). LCMS(ESI) m/z 616 [M+H]⁺.

Example 1094-Amino-5-[2-(2,3-dihydrobenzothiophen-7-yl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 2,3-dihydrobenzo[b]thiophene-7-carbaldehyde

7-Bromo-2,3-dihydrobenzo[b]thiophene (200 mg, 0.93 mmol) was dissolvedin tetrahydrofuran (2 mL), and an n-butyllithium solution (1.6 M hexanesolution, 1.4 mL, 2.2 mmol) was added thereto at −78° C., followed bystirring at −78° C. for 30 minutes. Thereafter, N,N-dimethylformamide(0.22 mL, 2.8 mmol) was added thereto at −78° C., followed by stirringat −78° C. for 20 minutes and at room temperature for 1 hour. Asaturated aqueous ammonium chloride solution, water, and ethyl acetatewere added to the reaction solution, and the aqueous layer was extractedwith ethyl acetate. The organic layer was washed with a saturated sodiumchloride aqueous solution, and dried over sodium sulfate, followed bydistilling off the solvent. The residue was purified by silica gelcolumn chromatography (developing solvent: ethyl acetate/hexane),thereby obtaining the title compound (74 mg, 49%) as a yellow oil.

¹H-NMR (CDCl₃) δ: 10.05 (1H, s), 7.62 (1H, d, J=7.5 Hz), 7.39 (1H, dd,J=7.5, 1.0 Hz), 7.18 (1H, t, J=7.5 Hz), 3.42-3.37 (2H, m), 3.31 (2H, t,J=7.6 Hz). LCMS (ESI) m/z 165 [M+H]⁺

Step 2: Synthesis of 7-ethynyl-2,3-dihydrobenzo[b]thiophene

The title compound was obtained as in step 1 of Example 51, except that2,3-dihydrobenzo[b]thiophene-7-carbaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.25 (1H, d, J=7.6 Hz), 7.15 (1H, dd, J=7.6, 1.0 Hz),6.96 (1H, t, J=7.6 Hz), 3.40-3.31 (5H, m).

Step 3: Synthesis of Example Compound 109

The title compound was obtained as in step 10 of Example 93, except that7-ethynyl-2,3-dihydrobenzo[b]thiophene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.15 (1H, s), 7.60 (1H, s), 7.23 (1H, d, J=7.6 Hz),7.20-7.17 (1H, m), 7.02 (1H, dd, J=7.6, 7.6 Hz), 4.97-4.88 (1H, m),4.43-4.40 (1H, m), 4.02-4.00 (1H, m), 3.44-3.34 (4H, m), 3.29-3.23 (1H,m), 3.20-3.15 (1H, m), 2.48-2.41 (1H, m), 2.32-2.28 (1H, m), 1.86-1.78(1H, m). LCMS (ESI) m/z 501 [M+H]⁺.

Example 1108-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]-3-oxa-8-azabicyclo[3,2,1]octaneStep 1: Synthesis of8-(4-ethynyl-3,5-difluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane

The title compound was obtained as in step 1 of Example 23, except that3-oxa-8-azabicyclo[3.2.1]octane was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.23 (2H, dd, J=13.6, 3.3 Hz), 4.01-3.98 (2H, m), 3.81(2H, d, J=11.2 Hz), 3.53 (2H, d, J=11.2 Hz), 3.39 (1H, s), 2.16-2.01(4H, m). LCMS (ESI) m/z 250 [M+H]⁺

Step 2: Synthesis of8-(3-ethoxy-4-ethynyl-5-fluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane

The title compound was obtained as in step 1 of Example 34, except that8-(4-ethynyl-3,5-difluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octane wasused in place of 4-(4-ethynyl-3,5-difluorophenyl)morpholine.

¹H-NMR (CDCl₃) δ: 6.08 (1H, dd, J=12.1, 2.2 Hz), 6.00 (1H, s), 4.08 (2H,q, J=7.0 Hz), 4.01 (2H, d, J=2.6 Hz), 3.85 (2H, d, J=11.0 Hz), 3.52 (2H,d, J=11.0 Hz), 3.39 (1H, d, J=5.9 Hz), 2.13-2.00 (4H, m), 1.45 (3H, t,J=7.0 Hz). LCMS (ESI) m/z 276 [M+H]⁺

Step 3: Synthesis of Example Compound 110

The title compound was obtained as in step 10 of Example 93, except that8-(3-ethoxy-4-ethynyl-5-fluorophenyl)-3-oxa-8-azabicyclo[3.2.1]octanewas used in place of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.50 (1H, s), 6.29 (1H, d, J=2.2 Hz),6.25 (1H, d, J=2.2 Hz), 4.97-4.92 (1H, m), 4.39 (1H, dd, J=8.4, 5.8 Hz),4.21-4.14 (4H, m), 4.01 (1H, dd, J=5.8, 3.8 Hz), 3.83 (2H, d, J=10.8Hz), 3.52 (2H, d, J=10.8 Hz), 3.30-3.12 (2H, m), 2.49-2.39 (1H, m),2.35-2.26 (1H, m), 2.10-1.99 (4H, m), 1.85-1.75 (1H, m), 1.45 (3H, t,J=7.0 Hz). LCMS (ESI) m/z 616 [M+H]⁺.

Example 1114-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-[2-methylsulfanyl-4-(1-piperidyl)phenyl]ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 4-fluoro-2-(methylthio)benzaldehyde

Sodium thiomethoxide (680 mg, 9.6 mmol) was suspended in toluene (10mL), and 2,4-difluorobenzaldehyde (1 g, 7.0 mmol) was added thereto,followed by stirring at 80° C. for 2 days. Ethyl acetate and water wereadded to the reaction solution. Then, the organic layer was washed witha saturated aqueous sodium hydrogen carbonate solution and saturatedsaline, and dried over sodium sulfate, followed by distilling off thesolvent. The residue was purified by silica gel column chromatography(developing solvent: ethyl acetate/hexane), thereby obtaining the titlecompound (499 mg, 42%) as a white solid.

¹H-NMR (CDCl₃) δ: 10.15 (1H, s), 7.82 (1H, dd, J=8.3, 6.1 Hz), 7.01 (1H,dd, J=10.1, 2.3 Hz), 6.95 (1H, dt, J=2.3, 8.3 Hz), 2.49 (3H, s). LCMS(ESI) m/z 171 [M+H]⁺

Step 2: Synthesis of 2-(methylthio)-4-(piperidin-1-yl)benzaldehyde

4-Fluoro-2-(methylthio)benzaldehyde (200 mg, 1.2 mmol) and potassiumcarbonate (220 mg, 1.6 mmol) were suspended in dimethylsulfoxide (2 mL),and piperidine (0.16 ml, 1.6 mmol) was added thereto at roomtemperature, followed by stirring at 80° C. for 2 hours and 30 minutes.Ethyl acetate and water were added at room temperature to the reactionsolution, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with a saturated sodium chloride aqueoussolution, and dried over sodium sulfate, followed by distilling off thesolvent. The residue was purified by silica gel column chromatography(developing solvent: ethyl acetate/hexane), thereby obtaining the titlecompound (345 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 9.99 (1H, s), 7.64 (1H, d, J=8.7 Hz), 6.68 (1H, dd,J=8.7, 2.3 Hz), 6.64 (1H, d, J=2.3 Hz), 3.43-3.40 (4H, m), 2.47 (3H, s),1.80-1.70 (6H, m). LCMS (ESI) m/z 236 [M+H]⁺

Step 3: Synthesis of 1-(4-ethynyl-3-(methylthio)phenyl)piperidine

The title compound was obtained as in step 1 of Example 51, except that2-(methylthio)-4-(piperidin-1-yl)benzaldehyde was used in place of2-fluoro-6-methoxybenzaldehyde.

¹H-NMR (CDCl₃) δ: 7.32 (1H, d, J=8.6 Hz), 6.68 (1H, d, J=2.5 Hz), 6.63(1H, dd, J=8.6, 2.5 Hz), 3.35 (1H, s), 3.24-3.21 (4H, m), 2.49 (3H, s),1.72-1.58 (6H, m). LCMS (ESI) m/z 232 [M+H]⁺

Step 4: Synthesis of Example Compound 111

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3-(methylthio)phenyl)piperidine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.53 (1H, s), 7.29 (1H, d, J=8.8 Hz),6.81 (1H, d, J=2.3 Hz), 6.75 (1H, dd, J=8.8, 2.3 Hz), 4.96-4.87 (1H, m),4.42-4.38 (1H, m), 4.02-4.00 (1H, m), 3.29-3.15 (6H, m), 2.52 (3H, s),2.48-2.40 (1H, m), 2.28-2.32 (1H, m), 1.85-1.77 (1H, m), 1.72-1.61 (6H,m). LCMS (ESI) m/z 572 [M+H]⁺.

Example 1124-[4-[2-[4-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-3-ethoxy-5-fluoro-phenyl]morpholine

The title compound was obtained as in step 10 of Example 93, except that4-(3-ethoxy-4-ethynyl-5-fluorophenyl)morpholine was used in place of1-ethynylnaphthalene.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.73 (1H, s), 6.65 (1H, t, J=6.0 Hz),6.56-6.39 (4H, m), 4.91-4.84 (2H, m), 4.69 (1H, d, J=4.4 Hz), 4.23-4.16(2H, m), 3.79 (1H, dd, J=8.4, 4.4 Hz), 3.74-3.68 (4H, m), 3.26-3.21 (4H,m), 3.12-3.04 (1H, m), 2.98-2.88 (1H, m), 2.27-2.17 (1H, m), 2.15-2.07(2H, m), 1.60-1.51 (1H, m), 1.36 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 590[M+H]⁺.

Example 1134-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(4-methoxy-2-methylsulfonyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis oftriisopropyl((4-methoxy-2-(methylsulfonyl)phenyl)ethynyl)silane

The title compound was obtained as in step 2 of Example 76, except that1-bromo-2-methanesulfonyl-4-methoxybenzene was used in place of5-(benzyloxy)-2-bromopyrimidine.

¹H-NMR (CDCl₃) δ: 7.61-7.59 (2H, m), 7.06 (1H, dd, J=8.5, 2.7 Hz), 3.88(3H, s), 3.33 (3H, s), 1.19-1.12 (21H, m). LCMS (ESI) m/z 367 [M+H]⁺

Step 2: Synthesis of 1-ethynyl-4-methoxy-2-(methylsulfonyl)benzene

The title compound was obtained as in step 3 of Example 76, except thattriisopropyl((4-methoxy-2-(methylsulfonyl)phenyl)ethynyl)silane was usedin place of 5-(benzyloxy)-2-((triisopropylsilyl)ethynyl)pyrimidine.

¹H-NMR (CDCl₃) δ: 7.64-7.62 (2H, m), 7.09 (1H, dd, J=8.5, 2.7 Hz), 3.90(3H, s), 3.53 (1H, s), 3.31 (3H, s). LCMS (ESI) m/z 211 [M+H]⁺

Step 3: Synthesis of Example Compound 113

The title compound was obtained as in step 10 of Example 93, except that1-ethynyl-4-methoxy-2-(methylsulfonyl)benzene was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.16 (1H, s), 7.72 (1H, s), 7.70 (1H, d, J=8.6 Hz),7.57 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=8.6, 2.8 Hz), 4.99-4.91 (1H, m),4.44-4.40 (1H, m), 4.03-4.01 (1H, m), 3.91 (3H, s), 3.30 (3H, s),3.39-3.24 (1H, m), 3.21-3.16 (1H, m), 2.50-2.42 (1H, m), 2.35-2.28 (1H,m), 1.87-1.79 (1H, m). LCMS (ESI) m/z 551 [M+H]⁺.

Example 1144-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfonyl-6-fluoro-4-pyrrolidin-1-yl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that1-(3-(ethylsulfonyl)-4-ethynyl-5-fluorophenyl)pyrrolidine was used inplace of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.13 (1H, s), 7.62 (1H, s), 6.99 (1H, d, J=2.6 Hz),6.64 (1H, dd, J=12.4, 2.6 Hz), 4.98-4.90 (1H, m), 4.43-4.39 (1H, m),4.02-4.00 (1H, m), 3.49 (2H, q, J=7.4 Hz), 3.39-3.34 (4H, m), 3.28-3.24(1H, m), 3.20-3.15 (1H, m), 2.48-2.40 (1H, m), 2.34-2.28 (1H, m),2.09-2.06 (4H, m), 1.85-1.77 (1H, m), 1.24 (3H, t, J=7.4 Hz). LCMS (ESI)m/z 622 [M+H]⁺.

Example 1154-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that(3R)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used inplace of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.54 (1H, s), 6.25 (2H, d, J=10.6 Hz),5.38 (1H, d, J=53.2 Hz), 5.04-4.95 (1H, m), 4.40 (1H, dd, J=8.4, 5.9Hz), 4.01 (1H, dd, J=5.5, 3.7 Hz), 3.64-3.10 (6H, m), 2.49-2.38 (1H, m),2.37-2.26 (2H, m), 2.22-2.12 (1H, m), 1.84-1.75 (1H, m). LCMS (ESI) m/z566 [M+H]⁺.

Example 1164-Amino-5-[2-[2,6-difluoro-4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of(3S)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine

The title compound was obtained as in step 1 of Example 23, except that(S)-3-fluoropyrrolidine was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.06 (2H, d, J=10.3 Hz), 5.38 (1H, d, J=53.5 Hz),3.62-3.39 (5H, m), 2.47-2.36 (1H, m), 2.28-2.07 (1H, m). LCMS (ESI) m/z226 [M+H]⁺

Step 2: Synthesis of Example Compound 116

The title compound was obtained as in step 10 of Example 93, except that(3S)-1-(4-ethynyl-3,5-difluorophenyl)-3-fluoropyrrolidine was used inplace of 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.11 (1H, s), 7.53 (1H, s), 6.22 (2H, d, J=10.6 Hz),5.38 (1H, d, J=53.2 Hz), 4.93-4.90 (1H, m), 4.42-4.37 (1H, m), 4.01 (1H,dd, J=5.5, 4.0 Hz), 3.62-3.15 (6H, m), 2.49-2.40 (1H, m), 2.34-2.27 (2H,m), 2.22-2.08 (1H, m), 1.84-1.76 (1H, m). LCMS (ESI) m/z 566 [M+H]⁺.

Example 1174-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 7-ethynyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

The title compound was obtained as in step 3 of Example 70, except that7-ethynyl-2,3-dihydrobenzo[b]thiophene was used in place of2-(ethylthio)-6-fluoro-4-(pyrrolidin-1-yl)benzaldehyde.

¹H-NMR (CDCl₃) δ: 7.57-7.51 (2H, m), 7.36 (1H, d, J=7.1 Hz), 3.57-3.52(3H, m), 3.35 (2H, t, J=7.2 Hz). LCMS (ESI) m/z 193 [M+H]⁺

Step 2: Synthesis of Example Compound 117

The title compound was obtained as in step 10 of Example 93, except that7-ethynyl-2,3-dihydrobenzo[b]thiophene 1,1-dioxide was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.15 (1H, s), 7.74 (1H, s), 7.64 (1H, t, J=7.6 Hz),7.58 (1H, d, J=7.6 Hz), 7.45 (1H, d, J=7.6 Hz), 5.00-4.89 (1H, m),4.44-4.40 (1H, m), 4.03-4.00 (1H, m), 3.62 (2H, t, J=7.1 Hz), 3.41 (2H,t, J=7.1 Hz), 3.22-3.11 (2H, m), 2.48-2.42 (1H, m), 2.32-2.26 (1H, m),1.87-1.77 (1H, m). LCMS (ESI) m/z 533 [M+H]⁺.

Example 1184-Amino-5-[2-[4-(azetidin-1-yl)-2,6-difluoro-phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3,5-difluorophenyl)azetidine was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.14 (1H, s), 7.56 (1H, s), 6.03 (2H, d, J=10.0 Hz),4.99-4.89 (1H, m), 4.40 (1H, dd, J=8.5, 5.6 Hz), 4.01 (1H, dd, J=5.6,3.7 Hz), 3.94 (4H, t, J=7.4 Hz), 3.28-3.09 (2H, m), 2.46-2.36 (3H, m),2.34-2.24 (1H, m), 1.85-1.72 (1H, m). LCMS (ESI) m/z 534 [M+H]⁺.

Example 1194-Amino-5-[2-[2,6-difluoro-4-(4-hydroxy-1-piperidyl)phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of 1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-ol

The title compound was obtained as in step 1 of Example 23, except thatpiperidin-4-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.36 (2H, d, J=11.2 Hz), 3.93-3.87 (1H, m), 3.58 (2H,dt, J=13.0, 4.9 Hz), 3.40 (1H, s), 3.06-3.00 (2H, m), 2.21-2.10 (1H, m),1.99-1.91 (2H, m), 1.65-1.55 (2H, m). LCMS (ESI) m/z 238 [M+H]⁺

Step 2: Synthesis of Example Compound 119

The title compound was obtained as in step 10 of Example 93, except that1-(4-ethynyl-3,5-difluorophenyl)piperidin-4-ol was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.19 (1H, s), 7.57 (1H, s), 6.57 (2H, d, J=11.5 Hz),4.98-4.89 (1H, m), 4.40 (1H, t, J=6.3 Hz), 4.01 (1H, dd, J=5.5, 3.8 Hz),3.85-3.78 (1H, m), 3.70-3.65 (2H, m), 3.30-3.14 (2H, m), 3.08-3.00 (2H,m), 2.49-2.40 (1H, m), 2.36-2.25 (1H, m), 1.97-1.88 (2H, m), 1.85-1.75(1H, m), 1.60-1.50 (2H, m). LCMS (ESI) m/z 578 [M+H]⁺.

Example 1204-Amino-5-[2-[2,6-difluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that(3R)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in placeof 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.22 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J=11.0 Hz),4.98-4.90 (1H, m), 4.55-4.51 (1H, m), 4.43-4.36 (1H, m), 4.01 (1H, dd,J=5.5, 3.8 Hz), 3.51-3.42 (2H, m), 3.40-3.33 (1H, m), 3.27-3.14 (3H, m),2.48-2.40 (1H, m), 2.34-2.26 (1H, m), 2.20-2.09 (1H, m), 2.08-2.00 (1H,m), 1.84-1.75 (1H, m). LCMS (ESI) m/z 564 [M+H]⁺.

Example 1214-Amino-5-[2-[2,6-difluoro-4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl]ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of(3S)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol

The title compound was obtained as in step 1 of Example 23, except that(S)-pyrrolidin-3-ol was used in place of morpholine.

¹H-NMR (CDCl₃) δ: 6.03 (2H, d, J=10.5 Hz), 4.64-4.60 (1H, m), 3.51-3.43(2H, m), 3.39 (1H, s), 3.34 (1H, dt, J=3.2, 9.0 Hz), 3.22 (1H, d, J=10.7Hz), 2.22-2.12 (1H, m), 2.12-2.05 (1H, m). LCMS (ESI) m/z 224 [M+H]⁺

Step 2: Synthesis of Example Compound 121

The title compound was obtained as in step 10 of Example 93, except that(3S)-1-(4-ethynyl-3,5-difluorophenyl)-pyrrolidin-3-ol was used in placeof 1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.23 (1H, s), 7.55 (1H, s), 6.20 (2H, d, J=10.7 Hz),4.97-4.89 (1H, m), 4.54-4.49 (1H, m), 4.46-4.35 (1H, m), 4.03-3.96 (1H,m), 3.51-3.41 (2H, m), 3.40-3.33 (1H, m), 3.27-3.12 (3H, m), 2.48-2.39(1H, m), 2.35-2.25 (1H, m), 2.19-2.09 (1H, m), 2.08-2.00 (1H, m),1.84-1.74 (1H, m). LCMS (ESI) m/z 564 [M+H]⁺.

Example 1228-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazineStep 1

The title compound was obtained as in step 10 of Example 93, except that8-ethynyl-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine was used inplace of 1-ethynylnaphthalene.

¹H-NMR (DMSO-D₆) δ: 8.17-8.12 (2H, m), 7.84 (1H, s), 6.77-6.64 (3H, m),6.53 (2H, s), 4.88 (1H, dd, J=18.7, 8.4 Hz), 4.43 (2H, t, J=4.2 Hz),4.21 (1H, dd, J=8.6, 5.3 Hz), 3.80 (1H, dd, J=5.1, 3.3 Hz), 3.25 (2H, t,J=4.2 Hz), 3.12-3.04 (1H, m), 2.96-2.89 (1H, m), 2.82 (3H, s), 2.24-2.19(1H, m), 2.15-2.08 (1H, m), 1.56 (1H, dd, J=20.9, 11.0 Hz). LCMS (ESI)m/z 532.3 [M+H]⁺.

Step 2: Synthesis of8-[2-[4-amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl]-7-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazinehydrochloride

The title compound hydrochloride was obtained as in step 5 of Example 1.

¹H-NMR (DMSO-D₆) δ: 8.45 (1H, s), 8.24 (1H, s), 6.81-6.74 (2H, m), 4.98(1H, dd, J=19.1, 8.8 Hz), 4.47 (2H, t, J=4.2 Hz), 4.20 (1H, dd, J=9.0,5.3 Hz), 3.80 (1H, dd, J=5.1, 2.9 Hz), 3.27 (2H, t, J=4.4 Hz), 3.08 (1H,dd, J=12.8, 6.6 Hz), 2.93 (1H, dd, J=12.5, 7.3 Hz), 2.84 (3H, s),2.29-2.22 (1H, m), 2.17-2.10 (1H, m), 1.58 (1H, dd, J=20.7, 10.8 Hz).LCMS (ESI) m/z 532.4 [M+H]⁺

Example 1234-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(1,1-dioxo-3,4-dihydro-2H-thiochromen-8-yl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 10 of Example 93, except that8-ethynyl thiochroman 1,1-dioxide was used in place of1-ethynylnaphthalene.

¹H-NMR (CD₃OD) δ: 8.16 (1H, s), 7.73 (1H, s), 7.57 (1H, d, J=7.7 Hz),7.50 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=7.7 Hz), 5.03-4.89 (1H, m),4.44-4.40 (1H, m), 4.04-4.02 (1H, m), 3.56-3.53 (2H, m), 3.30-3.25 (1H,m), 3.22-3.17 (1H, m), 3.09 (2H, t, J=6.0 Hz), 2.50-2.39 (3H, m),2.36-2.27 (1H, m), 1.87-1.79 (1H, m). LCMS (ESI) m/z 547 [M+H]⁺.

Example 1244-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(aminoethyl)tetrahydrofuran-3-ol

The title compound was obtained as in step 2 of Example 1, except that(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-olwas used in place of[(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol.

¹H-NMR (CD₃OD) δ: 8.09 (1H, s), 7.48 (1H, s), 6.52 (1H, t, J=7.0 Hz),4.37 (1H, dt, J=6.6, 4.0 Hz), 3.89 (1H, dt, J=7.0, 4.0 Hz), 2.91 (1H,dd, J=13.2, 4.0 Hz), 2.83 (1H, dd, J=13.2, 7.0 Hz), 2.66-2.59 (1H, m),2.33 (1H, ddd, J=13.9, 7.0, 3.7 Hz). LCMS (ESI) m/z 376 [M+H]⁺

Step 2: Synthesis oftert-butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamoyl]carbamate

The title compound was obtained as in step 3 of Example 1, except that(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(aminoethyl)tetrahydrofuran-3-olwas used in place of7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

¹H-NMR (DMSO-D₆) δ: 10.84 (1H, s), 8.09 (1H, s), 7.61 (1H, s), 6.76-6.61(2H, brm), 6.35 (1H, dd, J=8.8, 5.9 Hz), 5.33 (1H, d, J=4.0 Hz),4.28-4.26 (1H, brm), 3.90-3.87 (1H, m), 3.16-3.10 (2H, m), 2.59-2.52(1H, m), 2.11-2.06 (1H, m), 1.36 (9H, s). LCMS (ESI) m/z 555 [M+H]⁺

Step 3: Synthesis of Example Compound 124

tert-Butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamoyl]carbamate (40 mg, 0.072 mmol), 2-ethynyl-1,3-difluorobenzene(15 mg, 0.11 mmol), bis(triphenylphosphine)palladium (II) dichloride (10mg, 0.014 mmol), copper iodide (2.7 mg, 0.014 mmol), anddiisopropylethylamine (0.030 mL, 0.18 mmol) were suspended intetrahydrofuran (0.5 mL). The reaction solution was stirred at 70° C.overnight. Thereafter, trifluoroacetic acid (0.5 mL) was added theretoat room temperature, followed by stirring at room temperature overnight.After the solvent was distilled off, the residue was purified by silicagel column chromatography (developing solvent: methanol/chloroform),thereby obtaining the title compound (1.2 mg, 4%) as a white powder.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 8.00 (1H, s), 7.53-7.47 (1H, m),7.29-7.24 (1H, m), 7.18-7.15 (1H, m), 6.58 (2H, s), 6.43 (1H, dd, J=8.8,5.6 Hz), 5.35 (1H, d, J=4.1 Hz), 4.39-4.35 (1H, brm), 3.98-3.94 (1H,brm), 3.18-3.03 (2H, brm), 2.66-2.59 (1H, m). LCMS (ESI) m/z 465 [M+H]⁺.

Example 1254-Amino-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 3 of Example 124, except that1-ethynylnaphthalene was used in place of 2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.39 (1H, d, J=8.4 Hz), 8.35 (1H, s), 8.07 (1H, s),7.96 (1H, brs), 7.94 (1H, brs), 7.85 (1H, d, J=7.3 Hz), 7.67-7.46 (3H,m), 6.59 (1H, dd, J=7.7, 6.2 Hz), 4.62-4.59 (1H, m), 4.18-4.15 (1H, m),3.41-3.34 (2H, m), 2.77 (1H, ddd, J=13.9, 7.7, 6.2 Hz), 2.45 (1H, ddd,J=13.9, 6.2, 2.9 Hz). LCMS (ESI) m/z 479 [M+H]⁺.

Example 1264-[4-Amino-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2-(o-tolyl)thiazole

The title compound was obtained as in Example 2, except thattert-butyl-N-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamoyl]carbamate was used in place of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate.

¹H-NMR (CD₃OD) δ: 8.37 (1H, s), 8.26 (1H, s), 8.15 (1H, s), 8.04-8.01(1H, m), 7.66 (1H, d, J=7.7 Hz), 7.49-7.35 (3H, m), 6.68 (1H, dd, J=7.7,6.2 Hz), 4.61-4.58 (1H, m), 4.16 (1H, dt, J=5.9, 3.3 Hz), 3.44 (1H, dd,J=13.6, 4.0 Hz), 3.39 (1H, dd, J=13.6, 4.8 Hz), 2.72-2.65 (1H, m), 2.55(3H, s), 2.47 (1H, ddd, J=13.6, 6.2, 3.3 Hz). LCMS (ESI) m/z 502 [M+H]⁺.

Example 1274-Amino-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 3 of Example 124, except that1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.88 (1H, s), 7.37 (1H, ddd, J=8.8,8.4, 7.0 Hz), 7.19 (1H, dd, J=7.0, 5.5 Hz), 6.97 (1H, d, J=8.4 Hz), 6.91(1H, t, J=8.8 Hz), 6.57 (2H, s), 6.42 (1H, dd, J=8.4, 5.5 Hz), 5.37 (1H,d, J=4.0 Hz), 4.37 (1H, brs), 4.22 (2H, q, J=7.0 Hz), 3.99-3.93 (1H, m),3.22-3.04 (2H, m), 2.67-2.61 (1H, m), 2.17 (1H, dd, J=13.6, 5.5 Hz),1.37 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 491 [M+H]⁺.

Example 1284-Amino-5-[2-(2,6-difluorophenyl)ethynyl]-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol

(3aR,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one(1.0 g, 2.36 mmol) and cerium chloride heptahydrate (881 mg, 2.36 mmol)were suspended in methanol (5 mL), and sodium borohydride (92%, 146 mg,3.54 mmol) was added thereto with stirring at 0° C. After the mixturewas stirred at 0° C. for 2 hours, water (20 mL) was added thereto.Acetic acid was then added thereto until the pH of the reaction liquidbecame about 5. After the reaction liquid was partitioned between ethylacetate and water, the organic layer was separated. The obtained organiclayer was sequentially washed with a saturated aqueous ammonium chloridesolution and saturated saline, and dried over magnesium sulfate,followed by distilling off the solvent. The residue was purified bysilica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining the title compound (960 mg) as acolorless oil.

¹H-NMR (CDCl₃) δ: 7.72-7.66 (4H, m), 7.45-7.37 (6H, m), 5.85 (1H, s),4.88 (1H, d, J=5.5 Hz), 4.76 (1H, dd, J=6.2, 5.9 Hz), 4.58-4.55 (1H,brm), 4.39 (1H, d, J=14.7 Hz), 4.29 (1H, d, J=14.7 Hz), 1.37 (3H, s),1.34 (3H, s), 1.08 (9H, s). LCMS (ESI) m/z 425 [M+H]⁺

Step 2: Synthesis of7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

(3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(960 mg, 2.26 mmol), 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (632mg, 2.26 mmol), and triphenylphosphine (889 mg, 3.39 mmol) weredissolved in tetrahydrofuran (7 mL). Then, diisopropyl azodicarboxylate(667 μL, 3.39 mmol) was added thereto dropwise with stirring at 0° C.After the reaction liquid was stirred at room temperature for 14 hours,the reaction liquid was concentrated, and the residue was purified bysilica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining the title compound (1.33 g) as acolorless amorphous substance.

¹H-NMR (CDCl₃) δ: 8.69 (1H, s), 7.72-7.69 (4H, m), 7.49-7.39 (6H, m),7.15 (1H, s), 5.88-5.86 (1H, brm), 5.84-5.82 (1H, brm), 5.21 (1H, d,J=5.5 Hz), 4.56 (1H, d, J=5.5 Hz), 4.49 (2H, d, J=14.7 Hz), 1.44 (3H,s), 1.31 (3H, s), 1.11 (9H, s). LCMS (ESI) m/z 687 [M+H]⁺

Step 3: Synthesis of((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine(16.2 g, 23.6 mmol) was suspended in 1,4-dioxane (50 mL) and aqueousammonia (28%, 50 mL), followed by heating with stirring at 100° C. for24 hours in a pressure-resistant container. After the solvent wasdistilled off, tetrahydrofuran (50 mL) was added to the residue, andtetrabutylammonium fluoride (a 1 M tetrahydrofuran solution, 47 mL) wasadded thereto with stirring at room temperature, followed by stirring atroom temperature overnight. After the reaction solution was partitionedbetween ethyl acetate and water, the aqueous layer was separated, andextracted with ethyl acetate. The organic layers were combined andwashed with saturated saline, followed by distilling off the solvent.The residue was purified by silica gel column chromatography (developingsolvent: methanol/chloroform), thereby obtaining the title compound (7.4g) as a milky-white solid.

¹H-NMR (DMSO-D₆) δ: 8.12 (1H, s), 7.18 (1H, s), 6.63 (2H, brs),5.63-5.61 (1H, brm), 5.59-5.59 (1H, brm), 5.29 (1H, d, J=5.5 Hz), 5.06(1H, dd, J=5.7, 5.5 Hz), 4.49 (1H, d, J=5.9 Hz), 4.13 (2H, d, J=5.9 Hz),1.36 (3H, s), 1.25 (3H, s). LCMS (ESI) m/z 429 [M+H]⁺

Step 4: Synthesis oftert-butyl(((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(sulfamoyl) carbamate

((3aR,6R,6aS)-6-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(100 mg, 0.233 mmol), tert-butyl sulfamoylcarbamate (60 mg, 0.30 mmol),and triphenylphosphine (92 mg, 0.35 mmol) were dissolved intetrahydrofuran (1 mL). Then, diisopropyl azodicarboxylate (69 μL, 0.35mmol) was added thereto dropwise with stirring at 0° C. After thereaction liquid was stirred for 3 hours under ice-cooling, methanol (1mL) was added thereto, followed by stirring at room temperature for 10minutes. The reaction liquid was concentrated, and the residue waspurified by silica gel column chromatography (developing solvent:methanol/chloroform), thereby obtaining the title compound (60 mg) as acolorless amorphous substance.

¹H-NMR (CDCl₃) δ: 8.22 (1H, s), 6.91 (1H, s), 6.36-6.07 (4H, brm), 5.81(1H, brs), 5.69 (1H, brs), 5.32 (1H, d, J=5.9 Hz), 4.66-4.52 (3H, m),1.55 (9H, s), 1.48 (3H, s), 1.34 (3H, s). LCMS (ESI) m/z 607 [M+H]⁺

Step 5: Synthesis of Example Compound 128

tert-Butyl(((3aR,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(sulfamoyl) carbamate (60 mg, 0.099 mmol), 2-ethynyl-1,3-difluorobenzene(27.3 mg, 0.198 mmol), bis(triphenylphosphine)palladium (II) dichloride(3.5 mg, 0.005 mmol), copper iodide (1 mg, 0.0053 mmol), anddiisopropylethylamine (0.034 mL, 0.19 mmol) were suspended intetrahydrofuran (0.7 mL). After the reaction solution was stirred at 50°C. for 1 hour, the reaction liquid was concentrated, and the residue wasroughly purified by silica gel column chromatography (developingsolvent: methanol/chloroform). The obtained residue was dissolved atroom temperature in acetonitrile (0.5 mL) and concentrated hydrochloricacid (0.2 mL), followed by stirring at room temperature overnight. Afterthe reaction liquid was concentrated, the residue was purified by basicsilica gel column chromatography (developing solvent:methanol/chloroform), thereby obtaining the title compound (5.7 mg, 12%)as a white solid.

¹H-NMR (CD₃OD) δ: 8.16 (1H, s), 7.56 (1H, s), 7.45-7.38 (1H, m),7.11-7.05 (2H, m), 5.94 (1H, brs), 5.63 (1H, d, J=5.5 Hz), 4.68 (1H, d,J=5.5 Hz), 4.27 (1H, t, J=5.5 Hz), 3.95 (1H, d, J=16.5 Hz), 3.87 (1H, d,J=16.5 Hz). LCMS (ESI) m/z 477 [M+H]⁺.

Example 1294-Amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 5 of Example 128, except that1-ethoxy-2-ethynyl-3-fluorobenzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (CD₃OD) δ: 8.14 (1H, s), 7.45 (1H, s), 7.30 (1H, ddd, J=8.8, 8.4,6.6 Hz), 6.88 (1H, d, J=8.4 Hz), 6.78 (1H, t, J=8.8 Hz), 5.94 (1H, brs),5.61 (1H, d, J=4.8 Hz), 4.68 (1H, d, J=5.5 Hz), 4.27 (1H, dd, J=5.5, 4.8Hz), 4.24 (2H, q, J=7.0 Hz), 3.94 (1H, d, J=16.1 Hz), 3.91 (1H, d,J=16.1 Hz), 1.48 (3H, t, J=7.0 Hz). LCMS (ESI) m/z 503 [M+H]⁺.

Example 1304-Amino-7-[(1R,4R,5S)-4,5-dihydroxy-3-[(sulfamoylamino)methyl]cyclopent-2-en-1-yl]-5-[2-(2-fluoro-6-methylsulfanyl-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in step 5 of Example 128, except that2-ethynyl-1-fluoro-3-methanesulfanyl-benzene was used in place of2-ethynyl-1,3-difluorobenzene.

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.62 (1H, s), 7.41 (1H, ddd, J=8.8,8.8, 6.2 Hz), 7.15 (1H, d, J=8.8 Hz), 7.11 (1H, t, J=8.8 Hz), 6.80 (1H,t, J=5.7 Hz), 6.64 (2H, s), 5.74 (1H, s), 5.56 (1H, brs), 5.10 (1H, d,J=6.2 Hz), 5.01 (1H, d, J=6.2 Hz), 4.48 (1H, t, J=6.2 Hz), 4.11-4.06(1H, m), 3.73-3.59 (2H, m), 2.55 (3H, s). LCMS (ESI) m/z 505 [M+H]⁺.

Example 131[(2R,3S,4R,5R)-5-[4-amino-5-(2-phenylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfamate Step 1: Synthesis of((3aR,4R,6R,6aR)-6-(4-amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

[(3aR,4R,6R,6aR)-4-(4-Amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol(1 g, 2.3 mmol), phenylacetylene (354 mg, 3.5 mmol),bis(triphenylphosphine)palladium (II) dichloride (161 mg, 0.23 mmol),and copper iodide (44 mg, 0.23 mmol) were suspended in tetrahydrofuran(10 mL), Then, nitrogen purging was performed, and afterdiisopropylethylamine (0.78 mL, 4.6 mmol) was added thereto, thereaction solution was stirred at 70° C. for 2 hours. The reactionsolution was filtered through a celite bed and washed with chloroform,followed by distilling off the solvent. The residue was purified bysilica gel column chromatography (developing solvent: ethylacetate/hexane), thereby obtaining the title compound (800 mg, 85%) as ayellow amorphous substance.

¹H-NMR (CDCl₃) δ: 8.27 (1H, s), 7.51-7.49 (2H, m), 7.39-7.36 (3H, m),7.27-7.25 (1H, m), 6.52 (1H, d, J=10.7 Hz), 5.85-5.72 (2H, brs), 5.72(1H, d, J=5.1 Hz), 5.24 (1H, t, J=5.5 Hz), 5.12-5.09 (1H, m), 4.52-4.50(1H, brs), 4.00-3.96 (1H, m), 3.83-3.76 (1H, m), 1.64 (3H, s), 1.37 (3H,s). LCMS (ESI) m/z 407 [M+H]⁺

Step 2: Synthesis of((3aR,4R,6R,6aR)-6-(4-amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate

((3aR,4R,6R,6aR)-6-(4-Amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(50 mg, 0.12 mmol) was dissolved in acetonitrile (0.5 mL). Then,triethylamine (0.084 mL, 0.59 mmol) was added thereto at roomtemperature, and sulfamoyl chloride (0.5 M acetonitrile solution, 0.27mL) was added thereto in an ice bath. After the resulting mixture wasstirred for 40 minutes in an ice bath, the solvent was distilled off.Then, chloroform and an aqueous sodium hydrogen carbonate solution wereadded thereto, and the aqueous layer was extracted with a liquid mixtureof chloroform/methanol=5/1. The organic layer was washed with saturatedsaline and dried over sodium sulfate, followed by distilling off thesolvent. The residue was purified by silica gel column chromatography(developing solvent: ethyl acetate/hexane), thereby obtaining the titlecompound (39 mg, 67%) as a yellow amorphous substance.

¹H-NMR (CDCl₃) δ: 8.29 (1H, s), 7.52-7.49 (2H, m), 7.37-7.36 (3H, m),7.30 (1H, s), 6.08 (1H, d, J=2.7 Hz), 5.72-5.68 (2H, brs), 5.35 (1H, dd,J=6.3, 2.9 Hz), 5.13-5.11 (1H, m), 4.50-4.43 (3H, m), 1.62 (3H, s), 1.39(3H, s). LCMS (ESI) m/z 486 [M+H]⁺

Step 3: Synthesis of Example Compound 131

((3aR,4R,6R,6aR)-6-(4-Amino-5-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (380 mg, 0.79 mmol) was dissolved in tetrahydrofuran (4 mL),and a mixed solution (9.5 mL) of trifluoroacetic acid/water=4/1 wasadded thereto, followed by stirring at room temperature for 8 hours.After the solvent was distilled off, methanol was added, and the solventwas distilled off again. The residue was purified by basic silica gelcolumn chromatography (developing solvent:

methanol/chloroform), thereby obtaining the title compound (323 mg, 92%)as a white powder.

¹H-NMR (CD₃OD) δ: 8.15 (1H, s), 7.67 (1H, s), 7.55-7.52 (2H, m),7.39-7.37 (3H, m), 6.22 (1H, d, J=5.6 Hz), 4.90-4.80 (1H, m), 4.47-4.26(4H, m). LCMS (ESI) m/z 446 [M+H]⁺.

Example 132[(2R,3S,4R,5R)-5-[4-Amino-5-[2-(2,6-difluorophenyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfamate

The title compound was obtained as in Example 131, except that2-ethynyl-1,3-difluorobenzene was used in place of phenylacetylene.

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, s), 7.97 (1H, s), 7.55-7.50 (1H, m),7.31-7.25 (2H, m), 6.45-6.37 (2H, brs), 6.13 (1H, d, J=5.9 Hz),4.47-4.43 (1H, m), 4.28-4.23 (1H, m), 4.20-4.09 (5H, m). LCMS (ESI) m/z482 [M+H]⁺.

Example 133[(2R,3S,4R,5R)-5-[4-Amino-5-[2-(1-naphthyl)ethynyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methylsulfamate

The title compound was obtained as in Example 131, except that1-ethynylnaphthalene was used in place of phenylacetylene.

¹H-NMR (CD₃OD) δ: 8.41 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.94-7.90 (2H,m), 7.86 (1H, s), 7.80 (1H, d, J=4.0 Hz), 7.69-7.48 (3H, m), 6.29 (1H,d, J=5.1 Hz), 4.87-4.80 (1H, m), 4.52-4.26 (4H, m). LCMS (ESI) m/z 496[M+H]⁺.

Example 134[(2R,3S,5R)-5-[4-Amino-5-(2-phenylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamate

The title compound was obtained as in Example 131, except that(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-olwas used in place of[(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol.

¹H-NMR (CD₃OD) δ: 8.14 (1H, s), 7.67 (1H, s), 7.54-7.52 (2H, m),7.39-7.36 (3H, m), 6.65 (1H, dd, J=7.8, 6.1 Hz), 4.57-4.55 (1H, m), 4.32(1H, dd, J=11.0, 3.9 Hz), 4.29 (1H, dd, J=11.0, 3.9 Hz), 4.18 (1H, dt,J=3.2, 3.9 Hz), 2.60 (1H, ddd, J=13.7, 7.8, 6.1 Hz), 2.39 (1H, ddd,J=13.7, 6.1, 3.2 Hz). LCMS (ESI) m/z 430 [M+H]⁺.

Example 135[(2R,3S,5R)-5-[4-Amino-5-(1-benzylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamate Step 1: Synthesis of(2R,3S,5R)-5-(4-amino-5-(1-benzyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol

(2R,3S,5R)-5-(4-Amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol(100 mg, 0.265 mmol), tetrakis(triphenylphosphine)palladium(0) (15.3 mg,0.013 mmol), and1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (98mg, 0.34 mmol) were suspended in a 2 M aqueous sodium carbonate solution(0.66 mL) and 1,2-dimethoxyethane (2 mL), followed by stirring at 100°C. for 3 hours. The reaction solution was partitioned between ethylacetate and water, and the organic layer was washed with water, followedby concentration. The residue was purified by silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the target product (66 mg, 61%) as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.18 (1H, brs), 7.59 (1H, s), 7.44 (1H, s), 7.38-7.32(3H, m), 7.27-7.23 (2H, m), 6.90 (1H, s), 6.24 (1H, dd, J=8.8, 5.5 Hz),5.42-5.38 (2H, m), 5.32 (2H, s), 4.71 (1H, d, J=4.0 Hz), 4.15 (1H, s),3.91 (1H, d, J=12.5 Hz), 3.75 (1H, d, J=12.5 Hz), 3.05-2.98 (1H, m),2.25 (1H, dd, J=12.8, 5.5 Hz). LRMS (ESI) m/z 407 [M+H]⁺

Step 2: Synthesis of Example Compound 135

(2R,3S,5R)-5-(4-amino-5-(1-benzyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol(53 mg, 0.13 mmol) was dissolved in acetonitrile (1 mL). Then,1-aza-4-azoniabicyclo[2.2.2]octan-4-ylsulfonyl(tert-butoxycarbonyl)azanido:1,4-diazabicyclo[2.2.2]octane monohydrochloride (Reference: OrganicLetters, 2012, 10, 2626-2629) (114 mg, 0.26 mmol) was added thereto atroom temperature. After the reaction solution was stirred at 40° C.overnight, trifluoroacetic acid (0.3 mL) was added to the reactionliquid, followed by stirring at room temperature overnight. The reactionsolution was concentrated, and the residue was purified by silica gelcolumn chromatography (developing solvent: methanol/chloroform), therebyobtaining the title compound (4.7 mg, 7%) as a milky-white solid.

¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.88 (1H, s), 7.69 (1H, s), 7.41 (1H,s), 7.37-7.28 (5H, m), 6.71 (1H, t, J=7.0 Hz), 5.39 (2H, s), 4.57-4.52(1H, brm), 4.29-4.28 (2H, brm), 4.18-4.15 (1H, brm), 2.62-2.55 (1H, m),2.39-2.35 (1H, m). LCMS (ESI) m/z 486 [M+H]⁺.

Example 136[(1R,2R,3S,4R)-4-[4-Amino-5-(1-benzylpyrazol-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,3-dihydroxy-cyclopentyl]methylsulfamate

The title compound was obtained as in Example 135, except that((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanolwas used in place of(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol.

¹H-NMR (CD₃OD) δ: 8.10 (1H, s), 7.85 (1H, s), 7.66 (1H, s), 7.37-7.21(6H, m), 5.39 (2H, s), 5.07-4.98 (1H, m), 4.32 (1H, dd, J=8.2, 5.7 Hz),4.25 (2H, d, J=4.9 Hz), 4.05 (1H, dd, J=5.7, 3.5 Hz), 2.48-2.34 (2H, m),1.82-1.76 (1H, m). LCMS (ESI) m/z 500 [M+H]⁺.

Example 137[(2R,3S,5R)-5-[4-Amino-5-[1-[(3,4-dimethylphenyl)methyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamate Step 1: Synthesis of1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2mmol), cesium carbonate (2.18 g, 6.7 mmol), and3,4-dimethylbenzylchloride (0.98 mL, 6.7 mmol) were suspended inacetonitrile (10 mL). After the mixture was stirred at room temperatureovernight, the solid was filtered off through celite, and the filtratewas concentrated. The residue was purified by basic silica gel columnchromatography (developing solvent: ethyl acetate/hexane), therebyobtaining the title compound (1.29 g, 80%) as a light-yellow oil.

¹H-NMR (CDCl₃) δ: 7.80 (1H, s), 7.63 (1H, s), 7.14-6.97 (3H, m), 5.21(2H, s), 2.25 (3H, s), 2.25 (3H, s), 1.29 (12H, s). LRMS (ESI) m/z 313[M+H]⁺

Step 2: Synthesis of Example Compound 137

The title compound was obtained as in Example 135, except that1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewas used in place of1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

¹H-NMR (CD₃OD) δ: 8.12 (1H, s), 7.83 (1H, s), 7.66 (1H, s), 7.39 (1H,s), 7.11 (1H, d, J=7.8 Hz), 7.09 (1H, s), 7.02 (1H, d, J=7.8 Hz), 6.70(1H, dd, J=7.9, 6.2 Hz), 5.29 (2H, s), 4.57-4.52 (1H, m), 4.28 (2H, m),4.16 (1H, m), 3.60 (1H, dd, J=14.1, 7.1 Hz), 2.62-2.55 (1H, m),2.40-2.34 (1H, m), 2.25 (3H, s), 2.23 (3H, s). LCMS (ESI) m/z 514[M+H]⁺.

Example 138[(1R,2S,4R)-4-[4-Amino-5-[1-[(3,4-dimethylphenyl)methyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxy-cyclopentyl]methylsulfamate Step 1: Synthesis of(1S,2R,4R)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

The title compound was obtained as in step 2, step 5, and step 7 ofExample 93, except that(1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol was used in place of((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, s), 7.54 (1H, s), 6.64 (2H, brs),5.23-5.14 (1H, m), 4.73 (1H, brs), 4.61 (1H, brs), 4.01 (1H, m),3.48-3.44 (1H, m), 3.41-3.36 (1H, m), 2.23-2.16 (1H, m), 2.08-2.01 (1H,m), 1.96-1.85 (2H, m), 1.58-1.50 (1H, m). LCMS (ESI) m/z 375 [M+H]⁺

Step 2: Synthesis of Example Compound 138

The title compound was obtained as in Example 135, except that(1S,2R,4R)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanoland1-(3,4-dimethylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used in place of(2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-oland1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

¹H-NMR (CD₃OD) δ: 8.10 (1H, s), 7.79 (1H, s), 7.64 (1H, s), 7.26 (1H,s), 7.10 (1H, d, J=7.8 Hz), 7.09 (1H, s), 7.02 (1H, d, J=7.8 Hz),5.39-5.31 (1H, m), 5.29 (2H, s), 4.30-4.20 (3H, m), 2.53-2.46 (1H, m),2.38-2.15 (3H, m), 2.24 (3H, s), 2.23 (3H, s), 1.87-1.79 (1H, m). LCMS(ESI) m/z 512 [M+H]⁺.

Example 139[(2R,3S,5R)-5-[4-Amino-5-[2-(o-tolyl)thiazol-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamate

The title compound was obtained as in Example 135, except that4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o-tolyl)thiazole wasused in place of1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

¹H-NMR (CD₃OD) δ: 8.07 (1H, s), 8.04 (1H, s), 7.92 (1H, s), 7.67 (1H, d,J=7.3 Hz), 7.42-7.36 (2H, m), 7.34-7.30 (1H, m), 6.75 (1H, t, J=7.0 Hz),4.62-4.59 (1H, m), 4.39 (1H, dd, J=11.0, 3.2 Hz), 4.35 (1H, dd, J=11.0,3.2 Hz), 4.22 (1H, dd, J=6.1, 3.2 Hz), 2.59-2.56 (1H, m), 2.56 (3H, s),2.46-2.41 (1H, m). LCMS (ESI) m/z 503 [M+H]⁺.

Example 1404-Amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidineStep 1: Synthesis of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2-(ethylthio)-6-fluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate (39 mg, 0.064 mmol),ethyl(2-ethynyl-3-fluorophenyl)sulfane (23 mg, 0.13 mmol),bis(triphenylphosphine)palladium (II) dichloride (4.5 mg, 0.0064 mmol),copper iodide (1.2 mg, 0.0064 mmol), and diisopropylethylamine (0.022mL, 0.13 mmol) were suspended in tetrahydrofuran (1 mL). After thereaction solution was stirred at 50° C. for 3 hours, the solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (developing solvent: methanol/chloroform), therebyobtaining the title compound (28 mg, 66%) as a yellow powder.

¹H-NMR (CDCl₃) δ: 9.15 (1H, d, J=8.1 Hz), 8.52 (1H, s), 7.31 (1H, s),7.24-7.20 (1H, m), 7.06 (1H, d, J=8.1 Hz), 6.91 (1H, t, J=8.1 Hz),6.74-6.59 (2H, brm), 5.68 (1H, d, J=4.8 Hz), 5.30 (1H, dd, J=6.2, 4.8Hz), 5.11 (1H, dd, J=6.2, 2.2 Hz), 4.51 (1H, d, J=2.2 Hz), 3.72-3.66(1H, m), 3.60 (1H, d, J=12.8 Hz), 3.02 (3H, q, J=7.3 Hz), 1.61 (3H, s),1.45 (9H, s), 1.37 (3H, t, J=7.3 Hz), 1.35 (3H, s).

Step 2: Synthesis of Example Compound 140

tert-ButylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-((2-(ethylthio)-6-fluorophenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate(55 mg, 0.0829 mmol) was suspended with stirring under ice-cooling in1,4-dioxane (0.5 mL) and water (0.5 mL) while oxone (102 mg, 0.166 mmol)was added thereto. After the reaction liquid was stirred at roomtemperature for 3 hours, the reaction solution was partitioned betweenethyl acetate and water, and the organic layer was extracted. After thesolvent was distilled off, acetonitrile (0.5 mL), water (0.1 mL), andtrifluoroacetic acid (0.5 mL) were sequentially added to the residue,and the reaction solution was stirred at room temperature for 3 hours.The reaction liquid was concentrated, and the residue was purified bybasic silica gel column chromatography (developing solvent:methanol/chloroform), thereby obtaining the title compound (20 mg) as alight-yellow solid.

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, s), 8.04 (1H, s), 7.82 (2H, d, J=8.1 Hz),7.77 (2H, t, J=8.1 Hz), 7.70 (1H, dd, J=8.1, 5.5 Hz), 7.35 (1H, dd,J=7.7, 4.8 Hz), 6.58 (2H, s), 5.92 (1H, d, J=7.0 Hz), 5.38 (1H, d, J=6.2Hz), 5.22 (1H, brs), 4.62-4.58 (1H, m), 4.09-4.07 (1H, brm), 4.05-4.02(1H, m), 3.49 (2H, q, J=7.3 Hz), 3.22-3.17 (1H, m), 3.14-3.06 (1H, m),1.14 (3H, t, J=7.3 Hz). LCMS (ESI) m/z 555 [M+H]⁺.

Example 1414-Amino-5-[2-(4-benzyloxy-2-methylsulfonyl-phenyl)ethynyl]-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]pyrrolo[2,3-d]pyrimidineStep 1: (5-(Benzyloxy)-2-iodophenyl)(methyl)sulfane

The title compound was obtained as in step 1 of Example 76, except that4-iodo-3-(methylsulfanyl)phenol was used in place of2-bromopyrimidin-5-ol.

¹H-NMR (CDCl₃) δ: 7.63 (1H, d, J=8.6 Hz), 7.43-7.34 (5H, m), 6.74 (1H,d, J=2.9 Hz), 6.51 (1H, dd, J=8.6, 2.8 Hz), 5.06 (2H, s), 3.63 (3H, s).LCMS (ESI) m/z 356 [M+H]⁺

Step 2: Synthesis of (5-(benzyloxy)-2-ethynylphenyl)(methyl) sulfane

The title compound was obtained as in step 2 and step 3 of Example 76,except that (5-(benzyloxy)-2-iodophenyl)(methyl)sulfane was used inplace of 5-(benzyloxy)-2-bromopyrimidine.

¹H-NMR (CDCl₃) δ: 7.41-7.34 (6H, m), 6.76 (1H, d, J=2.3 Hz), 6.69 (1H,dd, J=8.4, 2.3 Hz), 5.08 (2H, s), 3.39 (1H, s), 2.45 (3H, s). LCMS (ESI)m/z 255 [M+H]⁺

Step 3: Synthesis of Example Compound 141

The title compound was obtained as in Example 140, except that(5-(benzyloxy)-2-ethynylphenyl)(methyl)sulfane was used in place ofethyl(2-ethynyl-3-fluorophenyl)sulfane.

¹H-NMR (CD₃OD) δ: 8.20 (1H, s), 7.82 (1H, s), 7.73 (1H, d, J=8.4 Hz),7.67 (1H, d, J=2.8 Hz), 7.47 (2H, d, J=6.8 Hz), 7.42-7.32 (4H, m), 5.23(2H, s), 5.05-4.95 (1H, m), 4.43-4.39 (1H, m), 4.03-4.00 (1H, m), 3.30(3H, s), 3.27-3.12 (2H, m), 2.50-2.42 (1H, m), 2.32-2.28 (1H, m),1.87-1.79 (1H, m). LCMS (ESI) m/z 627 [M+H]⁺.

Example 1424-Amino-7-[(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoylamino)methyl]cyclopentyl]-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in Example 140, except thattert-butylN-(((3aR,4R,6R,6aS)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate was used in place of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate.

¹H-NMR (DMSO-D₆) δ: 8.13 (1H, s), 7.99 (1H, s), 7.81 (1H, d, J=8.1 Hz),7.76 (1H, t, J=8.1 Hz), 7.68 (1H, dd, J=8.1, 5.1 Hz), 6.63 (1H, t, J=6.2Hz), 6.50 (2H, s), 4.89 (2H, d, J=7.0 Hz), 4.67 (1H, d, J=4.4 Hz),4.27-4.22 (1H, m), 4.08 (1H, q, J=5.3 Hz), 3.79-3.76 (1H, m), 3.49 (2H,q, J=7.3 Hz), 3.10-3.03 (1H, m), 2.94-2.87 (1H, m), 2.24-2.17 (1H, m),2.12-2.06 (1H, m), 1.60-1.52 (1H, m), 1.14 (3H, t, J=7.3 Hz). LCMS (ESI)m/z 553 [M+H]⁺.

Example 143 4-Amino-5-[2-(2-ethylsulfonyl-6-fluoro-phenyl)ethynyl]-7-[(2R,4S,5R)-4-hydroxy-5-[(sulfamoylamino)methyl]tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidine

The title compound was obtained as in Example 140, except thattert-butylN-[[(2R,3S,5R)-5-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-tetrahydrofuran-2-yl]methylsulfamoyl]carbamate was used in place of tert-butylN-(((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)sulfamoylcarbamate.

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 8.03 (1H, s), 7.87-7.83 (1H, m),7.80-7.75 (1H, m), 7.73-7.68 (1H, m), 7.16 (1H, t, J=5.9 Hz), 6.56 (2H,s), 6.43 (1H, dd, J=8.7, 5.7 Hz), 4.37 (1H, brs), 3.97 (1H, dt, J=2.0,4.6 Hz), 3.50 (2H, q, J=7.4 Hz), 3.20-3.14 (1H, m), 3.12-3.05 (1H, m),2.71-2.62 (1H, m), 2.21-2.16 (1H, m), 1.15 (3H, t, J=7.4 Hz). LCMS (ESI)m/z 539 [M+H]⁺.

Comparative Example

N-[(1S)-1-indanyl]-7-[(1R)-3a-hydroxy-4a-(sulfamoyloxymethyl)cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(MLN4924) was obtained by performing the synthesis in accordance withthe method disclosed in Patent Document 1.

The following tables show the structural formulae of the examplecompounds of the present application.

TABLE 1

X Y R₁ R₂ R₃ R₄ R₅ Example 1 single O NH OH OH

bond

Example 2 single O NH OH OH

bond

Example 3 single O NH OH OH

bond

Example 4 single O NH OH OH

bond

Example 5 single O NH OH OH

bond

Example 6 single O NH OH OH

bond

Example 7 single O NH OH OH

—CH₂—

Example 8 single O NH OH OH

bond

Example 9 single O NH OH OH

bond

Example 10 single O NH OH OH

TABLE 2

X Y R₁ R₂ R₃ R₄ R₅ Example 11 single O NH OH OH

bond

Example 12 single O NH OH OH

bond

Example 13 single O NH OH OH

bond

Example 14 single O NH OH OH

bond

Example 15 single O NH OH OH

bond

Example 16 single O NH OH OH

bond

Example 17 single O NH OH OH

bond

Example 18 single O NH OH OH

bond

Example 19 single O NH OH OH

bond

Example 20 single O NH OH OH

bond

TABLE 3

X Y R₁ R₂ R₃ R₄ R₅ Example 21 single O NH OH OH

bond

Example 22 single O NH OH OH

bond

Example 23 single O NH OH OH

bond

Example 24 single O NH OH OH

bond

Example 25 single O NH OH OH

bond

Example 26 single O NH OH OH

bond

Example 27 single O NH OH OH

bond

Example 28 single O NH OH OH

bond

Example 29 single O NH OH OH

bond

Example 30 single O NH OH OH

bond

TABLE 4

X Y R₁ R₂ R₃ R₄ R₅ Example 31 single O NH OH OH

—CH₂—

Example 32 single O NH OH OH

bond

Example 33 single O NH OH OH

bond

Example 34 single O NH OH OH

bond

Example 35 single O NH OH OH

bond

Example 36 single O NH OH OH

—CH₂—

Example 37 single O NH OH OH

bond

Example 38 single O NH OH OH

bond

Example 39 single O NH OH OH

bond

Example 40 single O NH OH OH

bond

TABLE 5

X Y R₁ R₂ R₃ R₄ R₅ Example 41 single O NH OH OH

bond

Example 42 single O NH OH OH

bond

Example 43 single O NH OH OH

bond

Example 44 single O NH OH OH

bond

Example 45 single O NH OH OH

bond

Example 46 single O NH OH OH

bond

Example 47 single O NH OH OH

bond

Example 48 single O NH OH OH

bond

Example 49 single O NH OH OH

bond

Example 50 single O NH OH OH

—CH₂—

Table 6

X Y R₁ R₂ R₃ R₄ R₅ Example 51 single O NH OH OH

bond

Example 52 single O NH OH OH

bond

Example 53 single O NH OH OH

bond

Example 54 single O NH OH OH

bond

Example 55 single O NH OH OH

bond

Example 56 single O NH OH OH

bond

Example 57 single O NH OH OH

bond

Example 58 single O NH OH OH

bond

Example 59 single O NH OH OH

bond

Example 60 single O NH OH OH

bond

TABLE 7

X Y R₁ R₂ R₃ R₄ R₅ Example 61 single O NH OH OH

bond

Example 62 single O NH OH OH

bond

Example 63 single O NH OH OH

bond

Example 64 single O NH OH OH

bond

Example 65 single O NH OH OH

bond

Example 66 single O NH OH OH

bond

Example 67 single O NH OH OH

bond

Example 68 single O NH OH OH

bond

Example 69 single O NH OH OH

bond

Example 70 single O NH OH OH

bond

TABLE 8

X Y R₁ R₂ R₃ R₄ R₅ Example 71 single O NH OH OH

bond

Example 72 single O NH OH OH

bond

Example 73 single O NH OH OH

bond

Example 74 single O NH OH OH

bond

Example 75 single O NH OH OH

bond

Example 76 single O NH OH OH

bond

Example 77 single O NH OH OH

bond

Example 78 single O NH OH OH

bond

Example 79 single O NH OH OH

bond

Example 80 single O NH OH OH

bond

TABLE 9

X Y R₁ R₂ R₃ R₄ R₅ Example 81 single O NH OH OH

bond

Example 82 single O NH OH OH

bond

Example 83 single O NH OH OH

bond

Example 84 single O NH OH OH

bond

Example 85 single O NH OH OH

bond

Example 86 single O NH OH OH

bond

Example 87 single O NH OH OH

bond

Example 88 single O NH OH OH

bond

Example 89 single O NH OH OH

bond

Example 90 single O NH OH OH

bond

TABLE 10

X Y R₁ R₂ R₃ R₄ R₅ Example 91 single O NH OH OH

bond

Example 92 single O NH OH OH

bond

Example 93 single C NH OH OH

bond

Example 94 single C NH OH OH

bond

Example 95 single C NH OH OH

bond

Example 96 single C NH OH OH

bond

Example 97 single C NH OH OH

bond

Example 98 single C NH OH OH

bond

Example 99 single C NH OH OH

bond

Example 100 single C NH OH OH

bond

TABLE 11

X Y R₁ R₂ R₃ R₄ R₅ Example 101 single C NH OH OH

bond

Example 102 single C NH OH OH

bond

Example 103 single C NH OH OH

bond

Example 104 single C NH OH OH

bond

Example 105 single C NH OH OH

bond

Example 106 single C NH OH OH

bond

Example 107 single C NH OH OH

bond

Example 108 single C NH OH OH

bond

Example 109 single C NH OH OH

bond

Example 110 single C NH OH OH

bond

TABLE 12

X Y R₁ R₂ R₃ R₄ R₅ Example 111 single C NH OH OH

bond

Example 112 single C NH OH OH

bond

Example 113 single C NH OH OH

bond

Example 114 single C NH OH OH

bond

Example 115 single C NH OH OH

bond

Example 116 single C NH OH OH

bond

Example 117 single C NH OH OH

bond

Example 118 single C NH OH OH

bond

Example 119 single C NH OH OH

bond

Example 120 single C NH OH OH

bond

TABLE 13

X Y R₁ R₂ R₃ R₄ R₅ Example 121 single C NH OH OH

bond

Example 122 single C NH OH OH

bond

Example 123 single C NH OH OH

bond

Example 124 single O NH OH H

bond

Example 125 single O NH OH H

bond

Example 126 single O NH OH H

bond

Example 127 single O NH OH H

bond

Example 128 double C NH OH OH

bond

Example 129 double C NH OH OH

bond

Example 130 double C NH OH OH

bond

TABLE 14

X Y R₁ R₂ R₃ R₄ R₅ Example 131 single O O OH OH

bond

Example 132 single O O OH OH

bond

Example 133 single O O OH OH

bond

Example 134 single O O OH H

bond

Example 135 single O O OH H

—CH₂—

Example 136 single C O OH OH

—CH₂—

Example 137 single O O OH H

—CH₂—

Example 138 single C O OH H

—CH₂—

Example 139 single O O OH H

bond

Example 140 single O NH OH OH

bond

TABLE 15

X Y R₁ R₂ R₃ R₄ R₅ Example 141 single C NH OH OH

bond

Example 142 single C NH OH OH

bond

Example 143 single O NH OH H

bond

Test Example 1: Nedd8 Conjugation Inhibitory Activity

A purified NAE (heterodimer of APPBP1 and UBA3) solution was prepared inthe following manner. The human APPBP1 gene (NCBI Reference Sequencenumber: NM_003905) region corresponding to amino acids 1 to 534 of humanAPPBP1 protein (NCBI Reference Sequence number: NP_003896, full length:534 amino acids) was inserted in pBacPAK9 (produced by Clontech) toconstruct a plasmid pBacPAK9-APPBP1 for expressing APPBP1 full-lengthprotein having a His tag and a TEV protease-recognition sequence at theN-terminus. Next, the human UBA3 gene (NCBI Reference Sequence number:NM_003968) region corresponding to amino acids 1 to 463 of human UBA3protein (NCBI Reference Sequence number: NP_003959, full length: 463amino acids) was inserted in pBacPAK9 to construct a plasmidpBacPAK9-UBA3 for expressing UBA3 full-length protein. ThepBacPAK9-APPBP1 or pBacPAK9-UBA3, and BacPAK6 DNA were cotransfectedinto insect cells (Sf9, produced by Clontech) to produce a recombinantbaculovirus containing APPBP1 or UBA3 gene. The APPBP1 gene recombinantbaculovirus was mixed with the UBA3 gene recombinant baculovirus, andthe resulting mixture was used to infect Sf9 cells. Thebaculovirus-infected Sf9 cells were incubated at 28° C. with shaking for72 hours in Grace's Insect Medium (produced by Gibco), and the collectedcells were suspended in a lysis buffer (50 mM Tris-HCl, 200 mM NaCl, and10% glycerol (pH 7.4)), followed by sonication. The sonicated cellsolution was centrifuged (40,000×g, for 30 minutes) to obtain thesupernatant as a crude extract. The crude extract was fractionated on aHisTrap HP column (produced by GE Healthcare) and a TALON Superflowcolumn (produced by Clontech), followed by the addition of a TEVprotease. Then, a His-tag cleavage reaction was performed at 4° C.overnight. The resulting solution was subjected to TALON Superflowcolumn chromatography, and the unadsorbed fraction was collected. Thisfraction was applied to a HiLoad 16/60 Superdex 75 prep grade columnequilibrated with 50 mM Tris-HCl, 200 mM NaCl, and 10% glycerol (pH7.4), and fractionated. A fraction containing an APPBP1/UBA3 complex wasconcentrated to obtain a purified NAE solution. The purification abovewas performed entirely at 4° C. The purified NAE solution was stored at−80° C. until use.

A purified GST-UBC12 solution was prepared in the following manner. Thehuman UBC12 gene (NCBI Reference Sequence number: NM_003969) regioncorresponding to amino acids 1 to 183 of human UBC12 protein (NCBIReference Sequence number: NP_003960, full length: 183 amino acids) wasinserted in pGEX-4T-2 (produced by GE Healthcare) to construct a plasmidpGEX-UBC12 for expressing UBC12 full-length protein having a GST tag atthe N-terminus. The pGEX-UBC12 was introduced into Escherichia coli(BL21 (DE3), produced by Stratagene), followed by culture at 37° C. for2 hours in the presence of 1 mM isopropyl-beta-D-thiogalactopyranoside(produced by Sigma-Aldrich). The collected Escherichia coli wassuspended in PBS, followed by sonication. The sonicated cell solutionwas centrifuged (40,000×g, for 5 minutes) to obtain the supernatant as acrude extract. A Glutathione Sepharose 4B carrier (produced by GEHealthcare) was added to the crude extract, and eluted with 50 mMTris-HCl (pH 7.9), 150 mM NaCl, and a 10 mM reduced glutathionesolution, followed by dialysis with 50 mM HEPES (pH 7.5) and a 0.05% BSAsolution to obtain a purified GST-UBC12 solution. The purified GST-UBC12solution was divided and stored at −80° C. until use.

The Nedd8 conjugation inhibitory activity was measured using anAlphaScreen assay system. Each of the purified NAE solution andGST-UBC12 solution was diluted with an assay buffer (50 mM HEPES (pH7.5), 5 mM MgCl₂, 1 mM DTT, 0.05% BSA) and added to a 384-well plate(#3673, produced by Corning) containing the test compound. Afterreaction at room temperature for 30 minutes, a solution obtained bydiluting ATP and Biotin-Nedd8 (produced by Boston Biochem) with theassay buffer was added thereto, followed by reaction for 90 minutes.

Detection mix (50 mM HEPES (pH 7.5), 0.05% BSA, 0.04 mg/mL anti-GSTAcceptor beads, 0.04 mg/mL Streptavidin Donor beads) (#6760603M,produced by Perkin Elmer) was added to each well in the same amount asthat of the reaction solution. Then, after reaction in a dark place atroom temperature for 1 hour, the fluorescence intensity was measuredusing an EnVision (produced by Perkin Elmer) multilabel plate reader.The Neddylation inhibition rate (%) achieved by the compound of thepresent invention was determined by the equation (equation A) belowusing the fluorescence signal of a test compound-free group as apositive control, and the fluorescence signal of the test compound- andATP-free group as a negative control. The concentration at which theNedd8 conjugation was reduced with the addition of each compound to 50%of the control was calculated (IC₅₀ (M)) and used as a relative index ofthe Nedd8 conjugation inhibitory activity.

Inhibition rate (%)=100−(T−B)/(C−B)×100  (equation A)

T: Signal in a well to which a test compound was addedC: Signal in a well to which a test compound was not addedB: Signal in a well to which a test compound and ATP were not addedTable 16 below show the results.

TABLE 16 IC50 (μM) Example 1 ≤0.0030 Example 2 0.0071 Example 8 0.029Example 10 0.024 Example 11 0.0078 Example 16 0.0096 Example 17 0.0054Example 18 0.027 Example 19 0.028 Example 20 0.0091 Example 21 0.015Example 22 ≤0.0030 Example 23 ≤0.0030 Example 24 ≤0.0030 Example 250.0048 Example 26 0.012 Example 29 0.0071 Example 30 0.027 Example 33≤0.0030 Example 34 0.024 Example 35 0.0041 Example 37 0.011 Example 380.0035 Example 39 ≤0.0030 Example 40 ≤0.0030 Example 41 ≤0.0030 Example42 0.0043 Example 43 0.0076 Example 44 0.029 Example 46 0.013 Example 470.0093 Example 49 0.018 Example 51 0.0035 Example 52 0.008 Example 540.0045 Example 55 ≤0.0030 Example 56 0.0053 Example 57 0.0058 Example 58≤0.0030 Example 59 0.0085 Example 60 0.0085 Example 61 0.0038 Example 620.016 Example 63 0.011 Example 64 0.0094 Example 66 0.0071 Example 670.0085 Example 69 0.015 Example 70 0.013 Example 71 0.014 Example 720.0044 Example 74 ≤0.0030 Example 75 ≤0.0030 Example 76 0.0051 Example79 0.0032 Example 80 0.014 Example 81 0.0056 Example 82 0.01 Example 830.019 Example 84 0.0097 Example 86 0.0054 Example 88 0.018 Example 890.011 Example 90 0.0056 Example 91 0.018 Example 94 0.021 Example 950.013 Example 96 0.0092 Example 97 0.0088 Example 98 0.0083 Example 990.019 Example 101 0.0076 Example 103 0.013 Example 104 0.0089 Example106 0.028 Example 110 0.013 Example 112 0.015 Example 113 ≤0.0030Example 114 ≤0.0030 Example 115 0.004 Example 116 0.0051 Example 1170.0043 Example 118 0.0068 Example 119 0.0042 Example 120 0.0043 Example121 0.0062 Example 122 0.02 Example 123 0.0091 Example 127 0.019 Example128 0.0033 Example 129 ≤0.0030 Example 130 0.004 Example 131 ≤0.0030Example 132 ≤0.0030 Example 133 0.025 Example 134 0.018 Example 1360.012 Example 137 0.019 Example 138 0.0065 Example 139 0.017 Example 1420.009 Example 143 0.024 Comp. Example 0.033

These results show that the compounds of the present invention exhibitedvery excellent Nedd8 conjugation inhibitory activity, compared with theComparative Example.

Test Example 2: Cell Growth Inhibition 1

The ability of test compounds to inhibit cell growth was determined byquantifying ATP from viable cells using a CellTiter-Glo™ LuminescentCell Viability Assay (#G7573, produced by Promega, Inc.). The humanacute T lymphoblastic leukemia CCRF-CEM cell lines (distributed byDainippon Pharmaceutical Co., Ltd. (currently Sumitomo Dainippon PharmaCo., Ltd.)) were seeded in a 96-well plate (#165305, produced by ThermoScientific Nunc) at a concentration of 1,000 cells/100 μL medium perwell. The cells were cultured in a 5% CO₂ incubator at 37° C. overnight,and the test compound was added thereto, followed by culture for another72 hours. A CellTiter-Glo™ Luminescent Cell Viability Assay reagent inan amount equal to the medium was added to each well, stirred for 5minutes on a shaker under shading conditions, and then left to stand atroom temperature for about 30 minutes. The luminescence intensity wasmeasured using a microplate reader (EnSpire™ Multimode Plate Reader,produced by PerkinElmer Japan Co., Ltd.), and used as an index of thenumber of viable cells in each well. The cell growth inhibition rate (%)achieved by the compound of the present invention was determined by thefollowing equation (equation B) by using the luminescence intensity of adrug untreated group (control) as a control. The concentration at whichthe number of cells are reduced with the addition of each compound to50% of the control was calculated (IC₅₀ (μM)).

Inhibition rate (%)=(C−T)/C×100  (equation B)

T: Luminescence intensity in a well to which a test compound was addedC: Luminescence intensity in a well to which a test substance was notaddedTable 17 below shows the results.

TABLE 17 CCRF-CEM IC50 (μM) Example 1 0.0062 Example 24 0.0027 Example25 0.0017 Example 29 0.004 Example 31 0.6 Example 32 2.5 Example 330.037 Example 34 0.0061 Example 35 0.002 Example 36 0.25 Example 370.006 Example 38 0.014 Example 39 0.0078 Example 40 0.019 Example 430.0027 Example 55 0.0022 Example 60 0.0051 Example 61 0.003 Example 640.0058 Example 66 0.0043 Example 70 0.015 Example 71 0.045 Example 720.088 Example 73 0.071 Example 74 0.16 Example 83 0.056 Example 84 0.23Example 85 0.038 Example 86 0.0055 Example 97 0.0031 Example 98 0.0073Example 120 0.035 Example 122 0.0088 Example 123 0.097 Example 1290.0021 Example 130 0.0032 Example 132 0.0018 Comp. Example 0.089

These results indicate that the compounds of the present inventioninhibited the growth of human leukemia CCRF-CEM cell lines.

Test Example 3: Carbonic Anhydrase II Enzyme Activity Inhibition

The carbonic anhydrase II enzyme activity inhibition was measured bymeasuring the esterase activity in which carbonic anhydrase II degrades4-nitrophenyl acetate (4-NPA) (produced by Sigma-Aldrich). A purifiedcarbonic anhydrase II solution (C6624, produced by Sigma-Aldrich) wasdiluted with an assay buffer (50 mM Tris-HCl (pH 7.5)) to 100 nM, and 50μL of the resulting solution was added to a 96-well plate (3695,produced by Costar) containing 40 μL of the test substance. Afterreaction at room temperature for 10 minutes, 10 μL of a 50 mM 4-NPAsolution was added to each well, followed by incubation for 30 minutesat room temperature. The 50 mM 4-NPA solution was prepared by 10-folddilution of a 500 mM 4-NPA solution, which was prepared at the time ofuse by dissolving the reaction product in DMSO, with the assay buffer.The absorbance at 405 nm was measured using a microplate reader(SpectraMax 250, produced by Molecular Devices) The activity level ofthe enzymatic hydrolysis reaction of ester was calculated using thefollowing equation (equation C) by subtracting the absorbance in thewell to which carbonic anhydrase II was not added.

Inhibition rate (%)=100−(T−B)/(C−B)×100  (equation C)

T: Absorbance in a well to which a test compound was addedC: Absorbance in a well to which a test compound was not addedB: Absorbance in a well to which a test substance and carbonic anhydraseII were not addedTable 18 below shows the results.

TABLE 18 IC50 (μM) Example 1 >1.0 Example 2 >1.0 Example 3 >1.0 Example6 >1.0 Example 10 >1.0 Example 12 >1.0 Example 14 >1.0 Example 24 0.4Example 25 >1.0 Example 29 >1.0 Example 35 >1.0 Example 36 >1.0 Example39 >1.0 Example 43 >1.0 Example 46 >1.0 Example 47 >1.0 Example 49 >1.0Example 50 >1.0 Example 52 >1.0 Example 55 >1.0 Example 60 >1.0 Example61 0.79 Example 64 >1.0 Example 66 >1.0 Example 86 >1.0 Example 88 >1.0Example 97 0.18 Example 98 >1.0 Example 120 >1.0 Example 122 >1.0Example 126 0.26 Example 127 0.34 Example 129 >1.0 Example 130 >1.0Example 134 >1.0 Example 136 0.031 Example 138 0.12 Example 139 0.41Example 143 >1.0 Comp. Example 0.012

These results confirm that the compound of the Comparative Exampleexhibited inhibitory activity against carbonic anhydrase II, whereas thecompounds of the Examples exhibited significantly reduced inhibitoryactivity.

Test Example 4: Cell Growth Inhibition 2

The ability of test compounds to inhibit cell growth was determined asin Test Example 2, except that the cell lines, the culture plate, andthe number of cells seeded per well were as shown in Table 19. For theculture plate, a 384-well plate (#3571, produced by Corning) was used.

Table 20 below shows the results.

TABLE 19 Seeding number (per 1 well) Cell Name Origin Obtained fromPlate (cells/μL medium) HCT116 Colon cancer ATCC 384 wells 250 cells/20μL Capan-1 Pancreatic cancer ATCC 384 wells 500 cells/20 μL A-427 Lungcancer ATCC 384 wells 250 cells/20 μL MDA-MB-453 Breast cancer ATCC 384wells 500 cells/20 μL LNCaP. FGC Prostate cancer DainipponPharmaceutical Co., Ltd. 384 wells 500 cells/20 μL (currently DS PharmaBiomedical Co., Ltd.) SJCRH30 Osteo- and soft tissue sarcoma ATCC 384wells 250 cells/20 μL U266B1 Multiple myeloma ATCC 384 wells 3000cells/20 μL  A-431 Skin cancer ATCC 384 wells 400 cells/20 μL MV-4-11Acute leukemia ATCC 384 wells 400 cells/20 μL DB B-cell lymphoma ATCC384 wells 1500 cells/20 μL 

TABLE 20 MDA- HCT116 Capan-1 A-427 MB-453 LNCaP.FGC Examples IC50 (μM)IC50 (μM) IC50 (μM) IC50 (μM) IC50 (μM) 1 0.016 0.73 0.022 0.46 0.65 250.0064 0.38 0.0054 0.48 0.5 55 0.012 0.87 0.007 0.094 0.26 130 0.0120.21 0.0064 0.032 0.46 29 0.014 0.56 0.049 0.64 0.28 122 0.018 0.890.022 0.076 0.51 64 0.014 1.2 0.091 0.14 0.68 Comp. 0.089 1.5 0.18 1.90.41 Example SJCRH30 U266B1 A-431 MV-4-11 DB Examples IC50 (μM) IC50(μM) IC50 (μM) IC50 (μM) IC50 (μM) 1 >10 0.11 0.73 0.021 0.26 25 5.10.22 0.12 0.011 0.12 55 0.55 0.031 0.48 0.0067 0.061 130 0.17 0.024 0.160.025 0.13 29 6.6 0.42 0.56 0.02 0.15 122 0.13 0.27 1.6 0.038 0.12 640.56 0.11 0.71 0.032 0.11 Comp. >10 1.4 0.75 0.11 0.56 Example

According to the above results, these compounds of the present inventioninhibited the growth of human colon cancer HCT116 cell line, humanpancreatic cancer Capan-1 cell line, human lung cancer A-427 cell line,human breast cancer MDA-MB-453 cell line, human prostate cancerLNCAP.FGC cell line, human osteo- and soft tissue sarcoma SJCRH30 cellline, human multiple myeloma U266B1 cell line, human skin cancer A-431cell line, human acute leukemia MV-4-11 cell line, and human diffuselarge B-cell lymphoma DB cell line.

Test Example 5: Antitumor Effect on Tumor Cells Transplanted into Mice 1

Human colon cancer HCT-116 cell lines were washed in PBS and suspendedat a concentration of 4×10⁷ cells/mL. 0.1 mL of this cell suspension wassubcutaneously implanted in the right chest of 6-week-oldBALB/cAJcl-nu/nu mice (produced by CLEA Japan, Inc.).

The length and the width of the implanted tumor and the body weight weremeasured. The tumor volume (TV) was calculated using the followingequation (equation D).

TV (mm3)=(length×width²)/2, wherein the unit of length and width ismm  (equation D).

When the TV reached 100 to 300 mm3, the animals were assigned to eachgroup in accordance with a stratified randomization procedure. The daywas considered day 1, the TV on the day was considered TV1, and the bodyweight on the day was considered BW1.

A required amount of the test compound was weighed to prepare anadministration solution. The compound of Example 1 was intravenouslyadministered in an amount of 5 mL per 1 kg of body weight on days 1, 4,8, and 11, and the compound of the Comparative Example was intravenouslyadministered in an amount of 10 mL per 1 kg of body weight on days 1, 4,8, and 11.

Thereafter, the length and the width of the tumor and the body weight(BWn) on day n were measured over time in the same manner, and the TVnof each mouse was calculated. Further, the relative tumor volume (RTVn)was calculated based on the TVn of each mouse using the followingequation (equation E); the treatment/control (T/C) value (%) wascalculated based on the mean RTVn of each drug administration groupusing the following equation (equation F); and the weight change rate(BWCn) was calculated using the following equation (equation G).

RTVn=TVn/TV1  (equation E)

T/Cn(%)=(mean RTV of each drug administration group on the last day ofthe test)/(mean RTV of the control group on the last day of thetest)×100  (equation F)

BWCn (%)=(BWn−BW1)/BW1×100  (equation G)

FIGS. 1 and 2, and Table 21 below show the results.

TABLE 21 Dose (mg/ Administration Number T/C15 BWC15 (%) Group kg/day)day of mice (%) Mean ± SD Control — — 5 100  1.5 ± 3.7 Comp. 120 1, 4,8, 11 5 36 −14.3 ± 5.1 Example Example 1 50 1, 4, 8, 11 5 23 −11.8 ± 4.7

An RTV15 comparison using Dunnett's test revealed that the RTV of theexample compound and the comparative example compound was significantlylower than that of the control. Further, a comparison usingAspin-Welch's t-test revealed that the RTV of Example 1 wassignificantly lower than that of the Comparative Example. The change ofthe body weight was within an acceptable degree, compared with thecontrol.

These results confirm the excellent tumor growth inhibitory effects ofthis compound of the present invention on human tumors.

Test Example 6: Antitumor Effect on Tumor Cells Transplanted into Mice 2

The tumor growth inhibitory effects on human tumors were evaluated as inTest Example 5, except that the hydrochloride compound obtained inExample 55 was used, and the animals were assigned to each group inaccordance with a stratified randomization procedure when the TV reached100 to 200 mm3.

FIGS. 3 and 4, and the following table (Table 22) show the results.

TABLE 22 Dose (mg/ Administration Number T/C15 BWC15 (%) Group kg/day)day of mice (%) Mean ± SD Control — — 5 100  0.9 ± 4.9 Comp. 120 1, 4,8, 11 5 51  −8.4 ± 3.2 Example Example 55 50 1, 4, 8, 11 5 26 −11.0 ±9.6

An RTV15 comparison using Dunnett's test revealed that the RTV of theexample compound and the comparative example compound was significantlylower than that of the control. Further, a comparison usingAspin-Welch's t-test revealed that the RTV of Example 55 wassignificantly lower than that of the Comparative Example. The change ofthe body weight was within an acceptable degree, compared with thecontrol.

These results confirm the excellent tumor growth inhibitory effects ofthis compound of the present invention on human tumors.

Test Example 7: Antitumor Effect on Tumor Cells Transplanted into Mice 3

The tumor growth inhibitory effects on human tumors were evaluated as inTest Example 5, except that the compound hydrochloride obtained inExample 122, the compound hydrochloride (Example 64), and human acutelymphoblastic leukemia (ALL) CCRF-CEM cell lines were used, and theanimals were assigned to each group in accordance with a stratifiedrandomization procedure when the TV reached 140 to 380 mm3.

At this time, the cell lines were washed in PBS, and suspended in 50%PBS and 50% Matrigel basement membrane matrix (#356237; produced by BDBiosciences) at a concentration of 1×10⁸ cells/mL. 0.1 mL of this cellsuspension was subcutaneously implanted to the right chest of 6-week-oldBALB/cAJcl-nu/nu mice (nude mice) (produced by CLEA Japan, Inc.). Thecompound hydrochloride (Example 122) was intravenously administered inan amount of 5 mL per 1 kg of body weight on days 1 and 8, and thecompound hydrochloride (Example 133) was intravenously administered inan amount of 5 mL per 1 kg of body weight on days 1 and 8. Theadministration solution of the Comparative Example was intravenouslyadministered in an amount of 5 mL per 1 kg of body weight on days 1, 4,8, and 11.

FIGS. 5 and 6, and Table 23 below show the results.

TABLE 23 Dose (mg/ Administration Number T/C15 BWC15 (%) Group kg/day)day of mice (%) Mean ± SD Control — — 5 100 7.8 ± 3.2 Comp. 120 1, 4, 8,11 5 47 6.1 ± 2.6 Example Example 64 50 1, 8 5 8 4.1 ± 1.6 Example 12250 1, 8 5 6 6.0 ± 4.5

An RTV comparison of Examples 120 and 133 was made using Dunnett's teston day 15. The results reveled that the RTV of Examples 120 and 133 onday 15 was significantly lower than that of the control. The change ofthe body weight was almost the same as that of the control.

These results confirmed that these compounds of the Examples exhibitedantitumor effects.

An RTV15 comparison using Dunnett's test revealed that the RTV of theexample compounds and the comparative example compound was significantlylower than that of the control. Further, the RTV of the compounds ofExamples 122 and 64 was compared with the RTV of the compound of theComparative Example using Dunnett's test. The results revealed that theRTV of Example 122 and Example 64 was significantly lower than that ofthe Comparative Example.

These results confirm the excellent inhibitory effects of the compoundsof the present invention on the growth of human tumors.

1. A compound or a salt thereof, represented by Formula (A) below:

wherein:

is a single bond or a double bond; X is —O—, —CH₂—, or —CH═; Y is —NH— or —O—; R₁ is hydrogen, fluorine, a hydroxy group, a cyano group, or an amino group; R₂ is hydrogen, fluorine, a hydroxy group, a cyano group, or an amino group; R₃ is a vinylene group, an ethynylene group, a C6-C14 arylene group, or a monocyclic or bicyclic heteroarylene group having at least one heteroatom selected from the group consisting of N, S, and O; R₄ is a bond, a methylene group, or a C3-C7 cycloalkylidene group; R₅ is a C3-C7 saturated cycloalkyl group that may have one or more R₆, a C6-C10 unsaturated cycloalkyl group that may have one or more R₆, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R₆; R₆ is selected from the group consisting of halogen, a hydroxy group, a cyano group, a C1-C6 alkyl group that may have one or more phenoxy group as a substituent, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O, a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more of either halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group as a substituent, an amino group, a mono- or di-(C1-C4 alkyl) amino group that may have one or more hydroxy group or phenyl group as a substituent, a C1-C6 alkoxy group that may have one or more of either halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O as a substituent, a benzyloxy group that may have one or more carbamoyl group as a substituent, a C1-C6 alkylthio group, a C1-C6 alkylsulfonyl group, and an aminosulfonyl group, wherein when two or more R₆ are present, the plurality of R₆ may be the same or different.
 2. The compound or a salt thereof according to claim 1, wherein in Formula (A), R₁ is hydrogen, fluorine, or a hydroxy group; R₂ is hydrogen, fluorine, or a hydroxy group; and R₃ is an ethynylene group, or a monocyclic or bicyclic heteroarylene group having 1 to 4 of at least one kind of heteroatom selected from the group consisting of N, S, and O.
 3. The compound or a salt thereof according to claim 1, wherein in Formula (A), R₁ is a hydroxy group; R₂ is hydrogen or a hydroxy group; R₃ is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S and O; R₅ is a C3-C7 saturated cycloalkyl group that may have one or more R₆, a C6-C10 unsaturated cycloalkyl group that may have one or more R₆, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R₆; and R₆ is halogen; a hydroxy group; a cyano group; a C1-C6 alkyl group that may have one or more phenoxy group as a substituent; a carbamoyl group; a C1-C6 alkoxycarbonyl group; a monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S and O; a monocyclic or bicyclic saturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more of either halogen, hydroxy group, carboxyl group, or C1-C6 alkyl group as a substituent; an amino group; a mono- or di-(C1-C4 alkyl) amino group that may have one or more hydroxy group or phenyl group as a substituent; a C1-C6 alkoxy group that may have one or more of either halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O as a substituent; a benzyloxy group that may have one or more carbamoyl group as a substituent; a C1-C4 alkylthio group; a C1-C4 alkylsulfonyl group; or an aminosulfonyl group, wherein when two or more R₆ are present, the plurality of R₆ may be the same or different.
 4. A compound or a salt thereof according to claim 1, wherein, in Formula (A), R₁ is a hydroxy group; R₂ is hydrogen or a hydroxy group; R₃ is an ethynylene group, or a monocyclic heteroarylene group having 2 of at least one kind of heteroatom selected from the group consisting of N, S and O; R₅ is a C3-C7 saturated cycloalkyl group that may have one or more R⁶; a C6-C10 unsaturated cycloalkyl group that may have one or more R⁶, or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R⁶; and R₆ is fluorine; chlorine; a hydroxy group; a cyano group; a C1-C6 alkyl group that may have one or more phenoxy group as a substituent; a carbamoyl group; a C1-C6 alkoxycarbonyl group; a pyridinyl group; an azetidinyl group; a hydroxy azetidinyl group; a thiomorpholinyl group; a dioxide thiomorpholinyl group; a methyl piperazinyl group; a hydroxy piperidinyl group; an oxopiperidinyl group; a piperidinyl group; a hydroxy pyrrolidinyl group; an oxopyrrolidinyl group; a pyrrolidinyl group; a carboxyl pyrrolidinyl group; a fluoro pyrrolidinyl group; a morpholinyl group; a 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl group; a 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group; an amino group; a methylamino group; an ethylamino group; an isopropylamino group; a hydroxyethylamino group; a dimethylamino group; a phenyl methylamino group; a C1-C6 alkoxy group that may have one or more of either halogen, C3-C7 saturated cycloalkyl group, or monocyclic or bicyclic unsaturated heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, S, and O as a substituent; a benzyloxy group that may have one or more carbamoyl group as a substituent; a C1-C4 alkylthio group; a C1-C4 alkylsulfonyl group; or an aminosulfonyl group, wherein when two or more R₆ are present, the plurality of R₆ may be the same or different.
 5. The compound or salt thereof according to claim 4, wherein said dioxide thiomorpholinyl group is a 1,1-dioxo-thiomorpholino group; said oxopiperidinyl group is a 4-oxo-1-piperidinyl group; and said oxopyrrolidinyl group is a 2-oxo-1-pyrrolidinyl group.
 6. A compound or a salt thereof according to claim 1, wherein, in Formula (A), R₁ is a hydroxy group; R₂ is a hydroxy group; R₃ is an ethynylene group; R₄ is a bond; R₅ is a C6-C10 unsaturated cycloalkyl group that may have one or more R₆; or a monocyclic or bicyclic unsaturated heterocycloalkyl group that has at least one heteroatom selected from the group consisting of N, S, and O, and that may have one or more R₆; and R₆ is selected from the group consisting of fluorine; chlorine; a hydroxy group; a cyano group; a methyl group; a 3-fluoro pyrrolidinyl group; a morpholinyl group; a thiomorpholinyl group; a 3-hydroxy azetidinyl group; an azetidinyl group; an amino group; a N-methylamino group; a C1-C6 alkoxy group that may have one or more of either halogen or C3-C7 saturated cycloalkyl group as a substituent; and a C1-C4 alkylthio group, wherein when two or more R₆ are present, the plurality of R₆ may be the same or different.
 7. An NAE inhibitor comprising the compound or a salt thereof according to claim 1, as an active ingredient in combination with an anticancer drug.
 8. A pharmaceutical composition comprising the compound or a salt thereof according to claim
 1. 